Non-ischemic cardiomyopathy encompasses a heterogeneous group of diseases, with a generally unfavorable long-term prognosis. Cardiac resynchronization therapy (CRT) is a useful therapeutic option for patients with symptomatic heart failure, currently recommended by all available guidelines, with outstanding benefits, especially in non-ischemic dilated cardiomyopathy. Still, in spite of clear indications based on identifying a dyssynchronous pattern on the electrocardiogram  a great proportion of patients are non-responders. The idea that multimodality cardiac imaging can play a role in refining the selection criteria and the implant technique and help with subsequent system optimization is promising. In this regard, predictors of CRT response, such as apical rocking and septal flash have been identified. Promising new data come from studies using cardiac magnetic resonance and nuclear imaging for showcasing myocardial dyssynchrony. Still, to date, no single imaging predictor has been included in the guidelines, probably due to lack of validation in large, multicenter cohorts. This review provides an up-to-date synthesis of the latest evidence of CRT use in non-ischemic cardiomyopathy and highlights the potential additional value of multimodality imaging for improving CRT response in this population. By incorporating all these findings into our clinical practice, we can aim toward obtaining a higher proportion of responders and improve the success rate of CRT. Non-ischemic cardiomyopathy encompasses a heterogeneous group of diseases, mostly with genetic determinism, with a generally unfavorable long-term prognosis due to the evolution to pump failure and sudden arrhythmic death, secondary to limited therapeutic options.Cardiac resynchronization therapy (CRT) is a useful therapeutic method for patients with heart failure, improving cardiovascular prognosis. The first set of evidence for the clinical benefits of CRT comes from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, which showed a significant improvement in symptoms of patients with heart failure and left ventricle ejection fraction (LVEF) < 35%, with a QRS duration over 130 ms ,3.These studies established the scientific bases for the 2016 European Society of Cardiology Heart Failure Guidelines that recommend CRT for patients with an LVEF below 35%, symptomatic despite optimal medical treatment with beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, aldosterone antagonists, and diuretics, in sinus rhythm, with a QRS duration of over 120 ms and left bundle branch block (LBBB) or non-LBBB morphology .When discussing CRT response, it is important to distinguish between cardiac reverse remodeling, which is frequently assessed by imaging, and the net clinical benefit, with impact on hard endpoints such as all-cause death or hospitalization for heart failure. In this regard, first reported in 2005 , CardiacTogether with echocardiography, over the last few years, new imaging modalities such as cardiac magnetic resonance (CMR) and nuclear imaging have proved their value in assessing mechanical dyssynchrony. Moreover, we anticipate that many new parameters will continue to emerge as tools to predict, guide, and assess CRT response. There are other papers that have addressed the contribution of imaging to this field, but this review provides an up-to-date synthesis of the latest evidence, with a focus on non-ischemic cardiomyopathy. Additionally, we discuss the hypothesis-generating studies that translated into trials examining hard clinical endpoints. By doing so, this paper highlights the potential additional value of multimodality imaging for improving CRT response and its clinical relevance in everyday practice. Still, future randomized control trials are needed in order to conclude if this approach can ultimately reduce costs and lead to a net clinical benefit.Non-ischemic dilated cardiomyopathy: Among cardiomyopathies, the greatest benefit of CRT is proven in non-ischemic dilated cardiomyopathy (DCM); see The MIRACLE trial included 113 patients with non-ischemic cardiomyopathy and 115 patients with ischemic cardiomyopathy. At baseline, the non-ischemic group had bigger LV volumes and lower LVEF when compared to the ischemic group . Interestingly, at 12 months after CRT implantation, the non-ischemic group exhibited a greater reduction in LV volumes and improvement in LVEF than those in the ischemic group . Additionally, patients in the non-ischemic group had a higher quality of life at 12 months after CRT implantation [The CARE–HF trial included 339 patients with ischemic heart disease and 473 patients with non-ischemic cardiomyopathy. The primary endpoint  was significantly reduced in the non-ischemic group, compared to the ischemic population (HR 0.46 vs. 0.71). Still, there was an important benefit for both populations in terms of the secondary outcome —HR 0.56 vs. 0.54 [n = 419; 236 ischemic and 183 non-ischemic) or medical therapy . At 12 months of follow up, there was a more important improvement in all the echocardiographic parameters, from a threefold increase in LVEF (+7.61% vs. +2.24%) to a reduction in mitral regurgitation (MR) and improvement in diastolic dysfunction [In the REVERSE trial, 610 patients were randomized to CRT (p = 0.001) among ischemic patients and a 44% reduction among non-ischemic patients (p = 0.002). In addition, it was observed that among non-ischemic patients there was a greater reduction in both end-systolic (37 ± 16%) and end-diastolic volume , with better response to CRT in women, diabetic patients, and those with an LBBB morphology [In MADIT–CRT, 1046 ischemic and 774 non-ischemic patients were investigated comparatively over a period of 2.4 years, showing a 34% reduction in the risk of heart failure and mortality (rphology . The benrphology .Hypertrophic cardiomyopathy (HCM): A minority of patients with HCM (5%) end up developing a dilated form (end-stage HCM), characterized by increased volumes, spherical remodeling, and severe functional impairment of LV defined by an LVEF < 50% .The first data on the benefit of biventricular pacing in HCM appeared in 2008 when Rogers et al. have investigated a group of 20 patients with CMH and LBBB and showed that biventricular pacing reduces the dimensions of the left atrium and left ventricle and can relieve the symptoms of heart failure . MoreoveAnother utility of CRT in patients with HCM may result from the diminution of the obstruction in left ventricular outflow tract (LVOT). In this regard, a pilot study published in 2011 that included 11 patients with hypertrophic obstructive cardiomyopathy (HOCM) with indication of implantable cardiac defibrillator (ICD) opted for the implantation of a CRT-D system. After six months of pacing, a reduction in NYHA class, peak and mean gradient was observed . In six patients, there was a reduction of more than 50% in the gradient, which fell below 40 mmHg .The Triple Chamber Pacing in Hypertrophic Obstructive Cardiomyopathy Patients (TRICHAMPION) trial is a prospective, single-blinded trial that included 25 patients and aimed to investigate the benefit of CRT-P in symptomatic patients with HOCM and severe LVOT obstruction, who were not candidates for ablative therapy. The primary endpoint was the relief of symptoms. The enrollment was closed in 2020, but the results have not yet been published .Left ventricular noncompaction cardiomyopathy (LVNC): LV noncompaction is frequently associated with the presence of heart failure and systolic dysfunction. A systematic review that identified 14 studies and 70 patients reported by 2018 showed, however, that CRT brings clinical benefits to these patients, and that those who respond to therapy benefit from improved systolic function, leading to improved contractility of noncompacted segments . This obp < 0.05), but without reduction in the end-diastolic and end-systolic volumes, improvement of right ventricular function or reduction of mitral regurgitation [Cardiac sarcoidosis: Data on CRT for patients with cardiac sarcoidosis are scarce. A study that included 19 patients with cardiac sarcoidosis who underwent CRT showed that there is a benefit for this category of patients, with the improvement of the LVEF from 28.8% to 35.9%  trial analyzed multiple echocardiographic parameters indicative of asynchronism by M mode and tissue Doppler imaging, which did not demonstrate benefits in predicting CRT response. The investigators considered that the negative results resided in the intra- and interobserver variability . SubsequAtrioventricular dyssynchrony: this is present and significant when atrial systole occurs much earlier than ventricular systole. This causes early and incomplete closure of the mitral valve, with the onset of diastolic mitral regurgitation and shortening of the filling time. Thus, atrial systole no longer contributes to diastolic filling. The ratio between filling time and the RR distance of <40% is significant. The presence of diastolic mitral regurgitation is an indicator of atrioventricular asynchronism and correlates with an unfavorable response to CRT .Interventricular dyssynchrony: this can be quantified by pulsed-wave Doppler and tissue Doppler imaging by measuring the time difference between the closure of the aortic and pulmonary valve .Intraventricular dyssynchrony: this represents a fundamental concept in CRT, and there are several parameters that suggest its presence.“True” LBBB: In patients with an LBBB on the electrocardiogram, it was observed that the myocardial deformation map differs depending on the etiology of the conduction disorder. Thus, in patients with ischemic LBBB, an initial septal contraction is observed with subsequent propagation to the lateral wall, while in patients with non-ischemic LBBB, there is an interruption of propagation in the anterior wall that contracts later, thus determining a U-shape activation (“horseshoe”). This latter type of activation is associated with a better response to CRT, and the identification of patients with “true” LBBB is important because they benefit the most from CRT.Over time, it has been observed that a small proportion of patients with idiopathic DCM respond very well after CRT—the so-called hyper responders—who achieve complete normalization of LVEF after resynchronization. This observation suggests that the presence of LBBB may be the causal factor of DCM for these patients . HoweverSeptal flash: In the context of LBBB, the first site of activation of the LV endocardium is called “the breakthrough site” and is located in the mid-apical septum. Therefore, the first notch on the surface ECG reflects the activation of the septal endocardium of the LV, and the second, the activation of the posterolateral wall. Since the free wall is not yet activated in the protosystole, the intraventricular pressure does not increase and the septum may contract at this breakthrough point. Later, when the pressure increases, the septum is pushed to the right. This early septal contraction is called “septal flash” and is associated with passive relaxation of the inferolateral wall, followed by contraction of this wall during passive relaxation at the septal level . This paApical rocking: Apical rocking, a movement identified in the apical four-chamber view, is characterized by a short septal movement of the apex due to early contraction of the septum in systole, followed by a longer lateral movement during ejection due to late contraction of the lateral wall, secondary to the presence of LBBB. This clockwise movement is typical of idiopathic DCM and indicates the presence of intraventricular asynchronism. The magnitude of the movement is directly proportional to the LV end-diastolic volume and is not influenced by the duration of the QRS complex. For non-ischemic patients, the presence of apical rocking predicts a benefit from CRT . RecentlFurthermore, 3D speckle-tracking echocardiography contributes to a better understanding of the pathophysiology of intraventricular asynchronism. A study that included 65 patients, of whom 20 with DCM and LVEF < 35% and QRS over 120 ms, 20 with DCM and LVEF < 35% and QRS below 120 ms, and 25 controls, used as indicators of intraventricular asynchronism the standard derivation of time to peak of the radial by 3D speckle tracking and time to peak rotation by 2D and 3D speckle tracking. It was observed that compared to control subjects, all patients with DCM exhibited an alteration of rotational indexes, the most affected being those with wide QRS, while LV torsion in patients with DCM and wide QRS was lower than in those with DCM and narrow QRS complex. Moreover, LV torsion after resynchronization was markedly improved in those with DCM and wide QRS, with a reduction in intraventricular asynchronism [CMR allows the evaluation of intraventricular dyssynchrony by three methods: myocardial tagging, displacement encoding with stimulated echoes (DENSE), and phase-contrast tissue velocity mapping .In 2013, Cochet et al. evaluated cardiac dyssynchrony on CMR in order to predict ventricular remodeling after CRT implantation. Asynchronism based on radial displacement and delayed enhancement data were used, while reverse remodeling was defined as a reduction in LV end-systolic volume by >15% at six months after device implantation. The study showed that the presence of intraventricular asynchronism independently predicted reverse remodeling, with a sensitivity of 67% and a specificity of 75%. Moreover, the identification of scar tissue by late gadolinium enhancement (LGE) was an independent predictor of the response, which was weak when the LV lead was placed at the level of the ventricular scar. Additionally, the presence of asynchronism was a more important predictor of CRT response than the duration of the QRS complex .Myocardial perfusion SPECT also predicts the response to CRT among patients with non-ischemic DCM with a sensitivity of 86% and a specificity of 80% . In addiA complete list of multi modality imaging parameters validated for CRT guidance can be found in A study published in 2015 by Lumens et al. started from the hypothesis that the difference in response between the ischemic and non-ischemic populations is based on the type of substrate. The study included 191 patients and showed that in the case of a true LBBB, the electromechanical substrate is a delay in conduction and thus the contraction of the posterolateral segment of up to 350 ms, which explains why these patients respond to CRT. In patients with a hypo contractility pattern in the lateral wall secondary to ischemic heart disease, the delay is not caused by a slowing in the propagation of electrical activation, but by the hypo contractile condition itself. This subgroup of patients benefits less from CRT and most often does not have a typical LBBB morphology, but rather nonspecific intraventricular conduction disorder . In the Therefore, it derives the need for a detailed analysis of the myocardial substrate before CRT implantation. This can be performed by echocardiography and CMR. Unlike ischemic cardiomyopathy, in which contractile asynchronism can derive from the presence of transmural or subendocardial scars that lead to hypokinetic or akinetic segments, non-ischemic patients often have a pattern of mid-myocardial or subepicardial scarring.p < 0.001) [By dobutamine stress echocardiography, one can assess the left ventricular contractile reserve (LVCR), a parameter that is independently associated with reverse remodeling after CRT. A meta-analysis that included eleven studies and 861 patients showed that LVCR can predict a favorable CRT response , Z score: 11.055, < 0.001) .Myocardial deformation imaging allows more accurate localization of scarred areas, which most often correlate with the localization obtained on CMR. Myocardial strain, longitudinal (GLS), radial (GRS), and circumferential (GCS), is a measure of myocardial deformation that is reduced in the presence of diseased myocardium. Specific cut-offs have been described for identifying the presence of a transmural scar as follows: <−10% for GLS, <−16.5% for GRS, and >−11.1% for GCS. In addition to predicting the myocardial substrate, Delgado-Montero et al. showed that values of GLS < −9% and GCS > −9% are associated with a higher risk of hospitalization, death, the necessity for LV assist device or heart transplantation, independent of CRT implantation . MoreoveThe presence of ventricular mid-myocardial fibrosis detected by CMR is an independent predictor of mortality for patients with DCM, both by pump deficiency and sudden cardiac death . Comparep < 0.0001) [A study published by Bleeker et al. that studied 40 patients with LVEF < 35%, QRS > 120 ms, and LBBB morphology, and showed that those with posterolateral scar identified on CMR are mostly non-responders, regardless of the presence or absence of contraction dyssynchronism, while over 80% of the patients without scar respond to CRT . Levya e 0.0001) .Another important study that included 75 patients who underwent CMR before the CRT implantation was published in 2014. Strain values based on the circumferential uniformity ratio (CURE) on cine DENSE were used to obtain scar data. In addition, mechanical stretch at the site of the LV probe and electrical activation delay was measured. After a follow-up period of 2.6 years, all parameters were predictors of CRT response, and a CURE index > 0.7 was associated with a 12-fold higher risk of death .Apart from the aforementioned cases, prior to the implantation of the resynchronization system, echocardiography can also be used to measure EF and ventricular volumes to determine the existence of wall motion abnormalities and quantify the severity of mitral regurgitation.LVEF before resynchronization may predict CRT response in patients with non-ischemic DCM. In a 2019 study, in which patients were followed by 2D and 3D echocardiography before and after implantation, it was observed that at an LVEF < 22.15%, no benefit was recorded after CRT, and in addition, the presence of mechanical asynchronism in these patients did not provide additional value to improve the patient selection process . DiscordThe degree of left ventricular dilation before resynchronization is an important predictor of post-implant remodeling, LVEF changes, and survival . An LVEDA study that included 100 non-ischemic patients with an indication for CRT showed that the presence of diastolic dysfunction before resynchronization can influence the response to CRT. Thus, patients with a delayed relaxation type 1 profile benefit the most, for those with a pseudonormal profile the response is more delayed, and patients with a restrictive type 3 profile do not benefit from the implant . An E/A In DCM, mitral regurgitation (MR) is favored by dilation of the heart cavities and by modification of the architecture of the mitral valve apparatus, especially the posterior displacement of the anterolateral papillary muscle. CRT reduces the degree of MR, which is associated with a longer period without the need for transplantation . The maiData on the effects of CRT on right ventricular dysfunction are contradictory. However, it appears that patients with right ventricular dysfunction and right intraventricular contraction asynchronism respond poorly to CRT, but this should not be considered an exclusion criterion ,60.In theory, the identification of the areas with the latest activation  by imaging could guide the positioning of the lead in order to succeed in recruiting the viable myocardium for the ventricular contraction to be as efficient as possible.p = 0.002) [Initially, the data seemed promising as the Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) trial, which included 220 patients, showed that guiding lead position by speckle-tracking imaging leads to an improvement in both echocardiographic (reduction of LV end-systolic volume) and clinical response . A year = 0.002) .However, the most recent data come from the ImagingCRT trial, a clinical trial that randomized 182 patients  to undergo CRT with the lead positioned in the area with the latest activation, as identified by echocardiography or conventionally; the trial showed no benefit for those patients in whom the LV lead was positioned after ultrasound guidance . Given tPositioning the lead by CMR guidance could be promising. Still, a study that included 99 patients with an indication for CRT and followed for 47 months, showed that CMR guidance does not bring any benefit on the risk of cardiovascular death or hospitalization for heart failure compared to classical guidance. However, in the subgroup of patients with LBBB on ECG and class NYHA > II, the benefit was in favor of CMR guidance  .p < 0.002), a more significant reduction of LVESV , of LVEDV , and an increase in the response rate  [.The SPECT Guided LV Lead Placement for Incremental Benefits to CRT Efficacy (GUIDE CRT) trial enrolled 194 consecutive patients from 19 centers in China who underwent a myocardial SPECT within seven days prior to resynchronization. In the SPECT-guided group, a better placement of the LV lead was observed  .The benefits of cardiac resynchronization derive mainly from changes in the myocardial activation sequence. In the CArdiac REsynchronization in Heart Failure (CARE–HF) trial, resynchronization parameters after implantation were optimized using echocardiography, and currently, echocardiography is the most widely used method for optimization . HoweverFor maximum optimization, the atrioventricular delay (AV delay) is set to obtain the maximum separation between the E and A waves on the transmitral pulsed-wave Doppler . After pSystem optimization can also be performed by setting the interventricular (VV) delay, an indicator of interventricular asynchronism. This can also be conducted by following the LVOT VTI by pulsed-wave Doppler and subsequent selection of the largest VTI. Both this method and tissue Doppler imaging can be used for optimization. For most patients, the most appropriate VV interval is LV pre-activation .Still, there is an increasing tendency to look for alternative methods of post-implant optimization of the CRT system.n = 31) or based on systolic asynchrony index derived from 3D echocardiography. At 12 months of follow up, no significant differences were observed on ventricular remodeling or clinical evolution of patients between the two groups [In a recent trial, 63 resynchronized patients were randomized to optimize the VV interval based on QRS complex duration   and methp < 0.001 for non-inferiority −10% margin). Moreover, the use of the SonR sensor was associated with a 35% reduction in hospitalizations for HF  [In this regard, the Clinical Trial of the SonRtip Lead and Automatic AV-VV Optimization Algorithm in the PARADYM RF SonR CRT-D (RESPOND–CRT), which randomized 998 patients for optimization using echocardiography or a SonR contractility sensor located in the right atrium, allows the optimization of both AV and VV intervals. Overall, the response rate was 75% in the SonR arm and 70.4% in the echocardiography-guided arm  randomized 401 resynchronized patients for optimization by echocardiography or hemodynamics multiple-replicated, beat-by-beat noninvasive blood pressure at baseline, aiming as primary endpoint peak exercise oxygen uptake at six months. The results showed that hemodynamic optimization is non-inferior to echocardiography, and through its potential for automation and reproducibility, it can serve as a useful tool for optimizing the CRT system .Another recent study started from the hypothesis that an electrophysiological implant with a left ventricular lead placed at the level of the latest activated segment, followed by an optimization of the VV interval after the implant, is non-inferior to an implant performed based on CT venous angiography, myocardial scintigraphy with 82Rubidium infusion, and speckle-tracking echocardiography. Thus, the 122 patients were randomized in a double-blind manner, noting that the electrophysiological guidance is non-inferior to six months. However, larger studies are needed to evaluate the feasibility of a purely electrical-guided CRT implantation .In conclusion, CRT has a proven benefit in non-ischemic cardiomyopathy, especially DCM. Echocardiography, CMR, and SPECT imaging can help with refining the patient selection criteria, the implant technique, and subsequent optimization of the system. The most important predictors of CRT response are the absence of mechanical asynchronism at the baseline, the presence of the scarring myocardium, and the suboptimal positioning of the left ventricular lead. In the years to come, we anticipate many new imaging parameters will continue to emerge in this field, and by incorporating some of them in our daily practice, we can aim toward obtaining a higher proportion of responders and improving the success rate of CRT. Future randomized control trials are needed in order to conclude if an imaging-based approach can ultimately reduce costs and contribute to a net clinical benefit.


Objectives: Left ventricular (LV) involvement has been associated with unfavorable prognosis in arrhythmogenic cardiomyopathy (ACM). We aim to evaluate LV mechanics by cardiovascular magnetic resonance-feature tracking (CMR-FT) in ACM patients with right ventricular (RV) dysfunction.Methods: We retrospectively recruited ACM patients diagnosed according to the revised Task Force Criteria (rTFC) from January 2015 to July 2017. All patients underwent CMR examinations and collections of clinical, electrocardiographic data. The strain and dyssynchrony parameters of LV and RV were analyzed. These patients were followed, and primary study outcome was defined as a composite of cardiovascular events (arrhythmic events and heart transplantation), secondary study outcome included arrhythmic events.Results: Eighty-nine ACM patients  were included. LV and RV ejection fractions were 49.12 ± 12.02% and 22.28 ± 10.11%, respectively. During a median (IQR) follow-up for 18.20 (11.60-30.04) months, 30 patients experienced cardiovascular events which included 22 patients who experienced arrhythmic events. Patients with cardiovascular events had impaired LV global longitudinal strain , impaired LV global circumferential strain , and greater LV longitudinal dyssynchrony (LVLD)  than those without. After adjusting for age, sex, and other confounding factors, LVLD ≥89.15 ms was an independent risk factor for cardiovascular events  and for arrhythmic events .Conclusions: LVLD by CMR-FT was an independent risk factor for cardiovascular and arrhythmic events in ACM patients in advanced stage, which could provide prognostic value for this subtype. Absence of prognostic value of conventional CMR parameters such as LVEF and RVEF.LV GLS ≥ −12.94% and LV GCS ≥ −13.11% were associated with cardiovascular events when adjusting for age and sex. However, it did not reach statistical significance after adjusting more confounders and in analysis of arrhythmic events.LVLD ≥ 89.15 ms assessed by CMR-FT was an independent risk factor for cardiovascular and arrhythmic events.Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disease with potential high risk of malignant ventricular arrhythmias and progressive heart failure at end-stage , 2. It iCardiac magnetic resonance (CMR) has emerged as an important tool in the evaluation of biventricular function due to its excellent myocardial-blood contrast and depiction of fibro-fatty tissue . TraditiWe retrospectively reviewed 106 patients ≥ 15 years old with suspected ACM referred for CMR examinations from January 2015 to July 2017 at Fuwai Hospital. Demographics, clinical information, 12-lead electrocardiography (ECG), and 24-h Holter monitoring data were collected from the medical records within 2 weeks of CMR examinations. The diagnostic standards for ACM were based on the revised task force criteria (rTFC) score with either two major criteria, one major and two minor criteria, or four minor criteria . All patAll patients were followed up via clinic visit, medical recording, or telephone interview (every 6 months). The primary study outcome was defined as a composite of cardiovascular events including heart transplantation, sudden cardiac death (SCD), resuscitated cardiac arrest, sustained ventricular tachycardia (SVT) (ventricular tachycardia lasting >30 s at >100 b.p.m. or with hemodynamic compromise requiring cardioversion), ventricular fibrillation/flutter, and appropriate implantable cardioverter-defibrillator (ICD) discharge. Appropriate ICD discharge was defined as appropriate if triggered by life-threatening arrhythmias: ventricular tachycardia above the programmed cutoff of the ICD  or ventricular fibrillation. The secondary study outcome was defined as arrhythmic events including SCD, SVT, ventricular fibrillation/flutter, and appropriate ICD discharge.CMR scans were performed on a 3-T scanner  and 3-T scanner  with a phased-array cardiovascular coil and electrocardiographic respiratory gating. All sequences were acquired with breath holding. Three single long-axis cine images  and 8 short-axis slices from the base of the mitral valve to the apex were acquired using balanced steady state free precession sequence (b-SSFP). Typical imaging parameters were as follows: field of view (FOV) = 320 × 320 mm, matrix = 192 × 224, repetition time (TR) = 3.3 ms, echo time (TE) = 1.7 ms, flip angle = 50°, number of cardiac frames = 25 per cardiac cycle, slice thickness = 8 mm, slice gap = 2 mm. Fat- and non-fat-suppressed fast spin-echo sequences were acquired identical with mid short-axis and LV four-chamber images with double-inversion recovery blood suppression pulses. Typical imaging parameters were as follows: FOV = 320 × 320 mm, matrix = 192 × 224, TR = 1-2 R-R intervals, TE = 10 ms, slice thickness = 8 mm, slice gap = 2 mm. The LGE images were acquired 10-15 min after intravenously injected gadolinium-DTPA  in identical long-axis and short-axis planes using segmented phase-sensitive inversion recovery (PSIR) sequence. Typical imaging parameters were: FOV = 380 × 320 mm, matrix = 256 × 162, TR = 8.6 ms, TE = 3.36 ms, flip angle = 25°, slice thickness = 8 mm, slice gap = 2 mm, nominal TI = 300-350 ms.Biventricular functions were analyzed using CVI42  by two radiologists with 8 years and 10 years of experience in CMR post-processing, who were blinded to clinical data. The endocardial and epicardial contours of both ventricles were manually traced at end-diastole and end-systole on 8 short-axis cine image slices. Papillary muscles were excluded from calculation of volumes. End-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction for both ventricles were generated automatically. All volumetric measurements were indexed to body surface area (BSA). Two, four chamber and eight short-axis LGE images were visually inspected by two independent observers to determine the presence of LGE in LV with excellent contrast between enhanced (bright) and normal myocardium (black). And the discrepancies between the two readers were adjudicated by a senior observer. The number of LGE segments in LV myocardium was also calculated according to the American Heart Association (AHA) 17-segment model.The CMR FT analysis was performed on the acquired cine images using CVI42 . End diastolic endo- and epicardial contours were traced semi-automatically in long-axis views  and short-axis view on cine images by investigators blinded to the clinical and CMR data. Adjustments were made after visual inspection during cine loop playback to ensure appropriate tracking of LV segments. For LV strain parameters, three long-axis and short-axis views of cine images were used to assess global and regional  peak strain in longitudinal, circumferential, and radial directions. The LV segmental strain parameters were provided according to the American Heart Association 16-segment model . In addit-test were performed for comparisons of normally distributed continuous variables. Non-parametric tests were performed using the Mann-Whitney U-test. Univariate and multivariate Cox proportional hazards regression analysis were used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of risk factors. The multivariable model was constructed to adjust for possible confounders with: (1) p-value < 0.1 in the univariate model; or (2) risk factors reported in previous studies. Receiver operating characteristics (ROC) analysis was applied to define the optimal cut-off values for dichotomizing continuous risk markers. Kaplan-Meier analyses of estimated event-free survival for the risk factors were conducted with log-rank test. The intra-class correlation coefficient (ICC) analysis was used to assess the inter- and intra-observer variability for biventricular strain parameters. A two-sided p-value of <0.05 was considered statistically significant. All the analyses were performed with the statistical software packages R  and EmpowerStats .All continuous variables were given as mean ± SD or as median values with interquartile range if normally distributed. Categorical variables were presented as percentages. The chi-square test or Fisher's exact test was used for comparisons of categorical variables, as appropriate. Student's n = 2), appropriate ICD discharge (n = 10), sustained ventricular tachycardia (n = 11), and heart transplantation (n = 7). Four of the seven heart transplantation patients experienced sustained ventricular arrhythmias prior to surgery. All patients were further divided into patients with (n = 30) or without (n = 59) events. Patients with events had a higher proportion of recent syncope (<6 months)  than that in the non-event group. No other significant differences were observed in terms of baseline characteristics among the two groups.Eighty-nine ACM patients, aged 40.40 ± 13.98 years, 67.42% male, were recruited in this study. The baseline characteristics of the patients were presented in 2, p = 0.054) compared with patients without events, while there were no other significant differences between the two groups in terms of conventional CMR parameters.As shown in p = 0.010), impaired LV GCS , and greater LVLD  in CMR-FT analysis . Representative cases from patients with and without events were shown in Compared with the non-event group, patients with events had significantly impaired LV GLS  and arrhythmic events (log rank p = 0.001). Patients with LV GLS ≥ −12.94% had worse survival free from cardiovascular events than those with LV GLS < −12.94% (log rank p = 0.009) and arrhythmic events (log rank p = 0.037). Patients with LV GCS ≥ −13.11% had worse survival free from cardiovascular events than those with LV GLS < −13.11% (log rank p = 0.006) and arrhythmic events (log rank p = 0.044). Moreover, we performed univariate and multivariate Cox proportional hazards analysis for LVLD, LV GLS, and LV GCS as shown in p = 0.002) and arrhythmic events  even after adjusting for confounding variables . When included as a categorical variable, LVLD ≥ 89.15 ms was an independent risk factor for cardiovascular events  and arrhythmic events  after adjusting for the above confounding variables. LV GLS ≥ −12.94% and LV GCS ≥ −13.11% was associated with cardiovascular events  and arrhythmic events  adjusting for age and sex. However, it did not reach statistical significance after adjusting more confounders in model II.As shown in The inter- and intra-observer variability for biventricular strain parameters are summarized in In the present study, we introduced CMR-FT technique in evaluating LV and RV mechanics in a sizable definite ACM cohort, in which all patients were recruited in a tertiary referral center and had advanced RV dysfunction. Thus, we underlined the prognostic value of LV mechanics in the setting of homogeneous RV functional status, which was different from previously reported study cohorts. In the absence of identified conventional risk stratification parameters, the present study showed LVLD ≥ 89.15 ms assessed by CMR-FT was an independent risk factor for cardiovascular and arrhythmic events. The prognostic value of LV GLS and LV GCS was less confirmed in this study cohort.In this study, we included patients with more advanced stages of RV dysfunction compared with other Western ACM populations , 9, 27. The presence of LV dysfunction in ACM patients is of clinical significance. Several studies have emphasized the incremental prognostic value of LV involvement in the risk stratification of ACM patients , 28, 29.Parameters reflecting RV structural and functional alterations have been revealed to be powerful prognostic risk factors of ACM patients such as RVEF, right ventricular fractional area change (RVFAC), and RV GLS , 30, 33.Several limitations should be stressed in this study. First, our study was evaluated in a single tertiary referral center, and was therefore subject to selection bias by including a highly selected population of ACM patients with advanced RV dysfunction or even biventricular dysfunction. Second, the follow-up period was relatively short to enable observation of robust outcome results. Thus, further validation of our results in studies containing larger sample size and longer follow-up duration might be warranted. Third, molecular genetic analysis was not included in this study.In this study, we evaluated LV mechanics by CMR-FT technique and highlighted its potential prognostic value in ACM patients in advanced stage. It was demonstrated that LVLD ≥ 89.15 ms assessed by CMR-FT was an independent risk factor for cardiovascular and arrhythmic events, however, the prognostic value of LV GLS and LV GCS was not fully confirmed in this study. CMR-FT derived LV longitudinal dyssynchrony could provide prognostic value for advanced ACM. However, the results of this exploratory analysis should be confirmed by future studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Fuwai Hospital Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.YS, LL, LC, and SZ made contributions to conception and design of study. YS drafted the manuscript and collected conventional CMR data. LL and LC were responsible for statistical analysis of the data. LC and RH made critical revisions of the manuscript. XC and KJ were in charge of post processing of CMR-FT analysis. ML and SZ made contribution to study conduction. All authors have read and approved the final manuscript.This study was supported by Grant Nos. 81930044, 81620108015, and 82100377 from the key projects of National Natural Science Foundation of China.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Late dilatation was defined as initially normal LVEDVi, which increased ≥ 20% at follow-up. Early dilatation was present in 7 patients (13%), whereas late dilatation occurred in 11 patients (21%). Patients with early LV dilatation had highest mortality (57%), whereas patients with late dilatation had similar mortality (27%) compared to patients without dilatation (26%). Multivariate Cox analysis showed that age (P < 0.001), ejection fraction at baseline (P < 0.01) and early dilatation (P < 0.01) were independent predictors of death. Early dilatation qualified as an exclusive independent predictor of long-term mortality after adjustment for age and ejection fraction . Early pre-discharge LV dilatation by CMR enabled strong long-term risk stratification after STEMI. The high mortality of early LV dilatation underscores the clinical importance of this post-infarction complication, which occurred despite PCI and contemporary medical therapy.To study the long-term prognosis of early pre-discharge and late left ventricular (LV) dilatation in patients with first ST-elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) and contemporary medical therapy. Long-term follow-up > 15 years was available in 53 consecutive patients (55 ± 13 years) with first STEMI. Late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (CMR) was obtained at baseline 5 ± 3 days and follow-up 8 ± 3 months after STEMI to measure LV function, volumes and infarct size. Early pre-discharge dilatation was defined as increased left ventricular end-diastolic volume index (LVEDVi) at baseline CMR with > 97 ml/mThe online version contains supplementary material available at 10.1007/s10554-020-02136-5. Left ventricular (LV) dilatation after acute myocardial infarction (AMI) is a complex and dynamic process with at least two components. Early LV dilatation occurs within the first 72 h after AMI, it is characterized by LV enlargement and thinning of the infarct area which results from stretching of the infarct zone due to slippage of necrotic myofibrils –3. Late We hypothesized that early LV dilatation present at pre-discharge is associated with an adverse prognosis, since this remodeling type occurs immediately after infarction which may represent the more profound myocardial damage compared to the remodeling type with initial normal LV volume and delayed LV enlargement.This longitudinal study analyzed the long-term prognostic impact of early pre-discharge and late LV dilatation up to > 15 years in patients with first ST-elevation myocardial infarction (STEMI) treated by PCI and contemporary medical therapy.The ethics committee of the Hamburger Ärztekammer approved the study (reference number PV3451) and all patients gave written informed consent. Sixty-eight consecutive patients with first STEMI were prospectively enrolled between April 2002 and June 2003. STEMI was defined by prolonged chest pain, peak creatine kinase MB more than twice the normal upper limit of 5 U/L, and 1.0 mm or more ST segment elevation in two or more leads on the initial 12-lead electrocardiography. Peak creatine kinase (CK), creatine kinase myocardial band were obtained. Patients were treated by primary percutaneous coronary intervention (PCI) (n = 58) or facilitated PCI after thrombolysis (n = 10). Adequate restoration of blood flow of the infarct-related artery was determined on coronary angiograms by two experienced observers  in consensus reading using the Thrombolysis in Myocardial Infarction (TIMI) trial criteria. The total ischemic time was recorded defined as the time between beginning of chest pain and reperfusion of the infarct-related artery . All pat3, gap 2 mm, 9–11 slices for full LV coverage, echo time = 1.8 ms, time to repetition = 3.6 ms. Inversion recovery LGE imaging was performed 10 min after injection of a dose of 0.1 mmol/kg gadopentetate dimeglumine  on end-diastolic short-axis using the following parameters: Voxel size 0.37 × 2.0 × 6 mm3, echo time = 3.4 ms, time to repetition = 7.6 ms. Inversion time 220–300 ms to null the signal intensity of normal myocardium. LGE images were obtained every other heartbeat to give time for more complete inversion recovery.CMR was performed in identical fashion at baseline and follow-up after AMI using a 1.5-T scanner . The imaging protocol included standard steady-state free-precession cine CMR in short axis for LV volume and mass measurement using the following parameters: voxel size 1.37 × 1.37 × 8 mmTwo investigators  independently and blindly analyzed each CMR set in random order using certified software . CMR parameters were indexed to the calculated body surface area (BSA) and are given as the mean of the two observers. Measurements of LV volumes and LV mass was performed in standard fashion on short-axis cine images . Infarct2 for males and > 90 ml/m2 for females, which were valid at the time of data acquisition  and third [Q3] quartiles and were compared using Mann–Whitney U test. Outcome was assessed using Kaplan–Meier graphs and a Cox proportional hazards model to compare groups and to obtain hazard ratios with Wald confidence intervals. A univariate analysis was performed to identify predictive parameters of survival and the combined endpoint of survival and MACE. In this univariate analysis, all parameters were selected that had a P < 0.05). No differences were observed between the groups in respect to the revascularization strategy by either primary PCI or facilitated PCI after thrombolysis  compared to patients with no dilatation with 76 ml/m2 . The LV mass index was higher in patients with early dilatation  and in patients with late dilatation  compared to patients with no dilatation . The infarct sizes of patients with early and late dilatation were higher with 26%LV  and 26%LV , respectively, compared to patients with no dilatation with 17%LV . No difference in infarct size was present between patients with early and late dilatation, P = 0.724). Patients with early dilatation had the largest MO size with 5.1%LV , however, MO was present in only 2 of 7 patients (29%) of this group.No differences were present in respect to age, sex and body surface area between patients with no dilatation , early n = 7, 13%) and late dilatation , baseline ejection fraction (P < 0.01), early dilatation (P = 0.056) and facilitated PCI after thrombolysis versus primary PCI (P = 0.172) were potential predictors of death and MACE  and LVESVi (P = 0.564) dropped out in the multivariate model whereas age (P < 0.001), ejection fraction at baseline (P < 0.01) and early dilatation (P < 0.05) were independent predictors of death. After adjustment for age and ejection fraction early dilatation was a significant predictor of mortality  and in the age and ejection fraction adjusted model  died during long-term follow-up and 16 30%) experienced the composite end point of death and MACE including one patient with resuscitation for sustained ventricular tachycardia and one patient with primary implantable cardioverter-defibrillator. Patients with early dilatation had the highest mortality rate (57%) compared to patients with late dilatation (27%) and to patients with no dilatation (26%)  during long-term follow-up, whereas patients with late or with no dilatation had similar mortality, illustrating the high risk of early dilatation and the more benign nature of late dilatation. Second, early dilatation was a potent independent predictor of death and MACE, pointing out the potential to timely identify patients with poor prognosis early after STEMI based on LV dilatation. Third, enzyme release and infarct size by CMR were not different in patients with early and late LV dilatation, suggesting that the amount of acute myocardial injury has no direct impact on the LV dilatation type.Our study showed that early pre-discharge LV dilatation was associated with high mortality rate (57%) during follow-up compared to 26% in patients with no LV dilatation. Furthermore, early dilatation was a potent predictor of death after adjustment for ejection fraction and age, which were also associated with death in the univariate Cox model. Other parameters, which were associated with reduced prognosis in previous studies, such as infarct size , presencBolognese et al. analyzed the impact of the LV dilatation type on prognosis after AMI treated by primary PCI . This stThe current data did not reveal difference in clinical and CMR parameters between patients with early and late dilatation. Especially, the infarct characteristics, such as enzyme release, infarct size and the revascularization strategy and success were not different between the two groups. Therefore, other factors must be responsible for the differential occurrence of early and late dilatation. It is possible, that patients with early or late dilatation had a longer the time to revascularization compared to patients with no remodeling. However, the total ischemic time was not different between groups.One limitation of our study is the relatively small number of patients with long follow-up, which may have affected the identification of other predictive factors associated with poor prognosis after AMI. Furthermore, we had to apply a stringent cut-off for the definition of late dilatation by using the upper 95% CI, since our unique long-time follow-up population is inherently relatively small. Nevertheless, milder degrees of early dilatation (e.g. the upper quartile) could also be associated with poor outcome in a larger study population.Another limitation is, that comprehensive information on CV risk factors and comorbidity and their changes during the follow-up period were not available.Patients with early pre-discharge LV dilatation, defined as increased LVEDVi at 5 days after infarction had highest mortality of 57% during long-term follow-up. Furthermore, early dilatation was an independent predictor of death and MACE, underlining the importance to reduce this post-infarction complication. Conversely, late LV dilatation had similar outcome compared to patients with no dilatation, indicating that this dilatation type is less prognostic relevant in the era of infarct treatment by PCI and contemporary medical therapy.The current study revealed that infarct characteristics, such as infarct size by CMR, enzyme release and the revascularization strategy and success were not different between patients with early and late LV dilatation. Therefore, other factors must be responsible for early LV dilatation, such as time to revascularization or amount of collateral flow during infarction. Further studies are needed to confirm occurrence and prognostic relevance of early pre-discharge LV dilatation after AMI in patients treated by the current standard of care and to better understand the causes of this LV dilatation type to prevent this deleterious complication in future.Supplementary file1 (sav 11 KB)Below is the link to the electronic supplementary material.


The lateral prefrontal cortex (LPFC) is disproportionately expanded in humans compared to non-human primates, although the relationship between LPFC brain structures and uniquely human cognitive skills is largely unknown. Here, we test the relationship between variability in LPFC tertiary sulcal morphology and reasoning scores in a cohort of children and adolescents. Using a data-driven approach in independent discovery and replication samples, we show that the depth of specific LPFC tertiary sulci is associated with individual differences in reasoning scores beyond age. To expedite discoveries in future neuroanatomical-behavioral studies, we share tertiary sulcal definitions with the field. These findings support a classic but largely untested theory linking the protracted development of tertiary sulci to late-developing cognitive processes. Tertiary sulci are shallow cortical folds that emerge late in gestation. Here the authors link prefrontal tertiary sulcal depth with reasoning scores in children and adolescents. These cross-species differences are especially pronounced in association cortices such as lateral prefrontal cortex (LPFC). LPFC is a late-developing cortical expanse that is enlarged in humans compared to non-human primates2 and is critical for cognitive control, executive function, reasoning, and goal-directed behavior6. Yet there is still much progress to be made in understanding how the development of evolutionarily new brain structures in the expanded human LPFC supports the development of complex, largely human, cognitive skills achieved by neural circuits within LPFC.A fundamental question in cognitive neuroscience is how the structure of the brain supports complex cognition. While much progress has been made in answering this question, especially in animal models, human brains differ in both their micro- and macrostructural properties from widely used animals in neuroscience research such as mice, marmosets, and macaques28. Tertiary sulci are the last to emerge in utero, and subsequently are often the shallowest and smallest class of cortical folds28. They are largely overlooked due to methodological difficulties in their identification (which we expand on further below)29. Due to these difficulties, very little is known regarding the role of tertiary sulci in human cognition, despite the fact that many tertiary sulci are evolutionarily new structures. We refer to tertiary sulci as evolutionarily new because they are identifiable in humans and non-human hominoids (great apes), but not in other non-human primates30 (see Supplementary Information for further details regarding dimples and lack of tertiary sulci in non-human primates).Of all the cognitive skills and anatomical features to focus on, we investigate the relationship between relational reasoning and macroanatomical structures in human cortex known as tertiary sulci. Sulci are commonly classified as primary, secondary, or tertiary based on their time of emergence in gestation31. Humans consistently outperform other species in tests of relational reasoning32, which relies on a distributed network involving LPFC that has expanded through primate evolution and that develops slowly over childhood and adolescence38. LPFC is considered critical to reasoning43 and developmental improvements in reasoning are associated with structural and functional connectivity between LPFC and lateral parietal cortex44.Here, we tested whether tertiary sulci in LPFC are behaviorally significant: that is, whether they relate to higher cognitive functioning. We focus on relational reasoning, which is the ability to extract common features across objects and conceptualize them in terms of their relation to each other9 proposed that morphological changes in tertiary sulci would likely be associated with the slow development of higher-order thinking and cognitive skills28. Fitting these criteria, relational reasoning continues to develop throughout childhood, while tertiary sulci emerge late in gestation and continue to develop after birth for a still undetermined period of time46. A relationship between relational reasoning and tertiary sulcal morphology would build on previous findings relating the development of relational reasoning to changes in LPFC cortical thickness and structural connectivity48. Furthermore, relational reasoning supports complex problem solving and scaffolds the acquisition of additional cognitive skills in children50. Thus, exploring if or how tertiary sulci contribute to the development of this cognitive skill may not only provide insight into a classic theory, but also advance understanding of the anatomical features underlying variability in the development of a wide range of other cognitive skills.As both reasoning and the LPFC exhibit protracted developmental trajectories in childhood, they serve as ideal targets to test a classic, yet largely unconsidered theory. Specifically, Sanides51, no study to date (to our knowledge) has tested the role of tertiary LPFC sulci in cognitive development. This gap likely persists for three key reasons. First, previous studies examining individual differences in the development of reasoning and anatomical variability in human LPFC39 implemented analyses that were averaged across individuals on standard neuroanatomical templates, which obscure tertiary sulci in LPFC25  using T1 magnetic resonance images (MRI) and cortical surface reconstructions—either in vivo or post-mortem—to visualize tertiary sulci, and (2) manually tracing/defining tertiary sulci on either T1 MRI images or cortical surface reconstructions (“Methods”)56. Third, as detailed below, the patterning of LPFC tertiary sulci has classically remained contentious until recent studies57.While recent studies suggest a link between the morphology of tertiary sulci in association cortices and cognitive functions,62 left tertiary LPFC sulci undefined or conflated with surrounding structures21 (“Methods”). For example, sulci consistent with the location of the modern definition of the posterior middle frontal sulcus (pmfs) were often considered the posterior end of the intermediate frontal sulcus (imfs)60. Functional and anatomical work by Petrides and colleagues63 has resolved these contentions by considering three components of the pmfs that are distinct from the imfs—a definition that additional recent work also supports25. The contention in classical definitions of tertiary sulci means that neuroanatomical atlases and neuroimaging software packages largely exclude tertiary sulci. In turn, tertiary sulci in LPFC have been excluded from most developmental cognitive neuroscience studies until the present study51. Nevertheless, there is increasing evidence that some tertiary sulci are functionally relevant in association cortices such as ventral temporal cortex11 (VTC), medial PFC64, and LPFC25 in adults, as well as behaviorally and clinically meaningful in medial PFC65. Irrespective of this mounting evidence that tertiary sulci are functionally and behaviorally relevant in association cortices within adults, it is largely unknown whether morphological features of tertiary sulci are linked to individual differences in behavior and cognition in a developmental cohort.Indeed, earlier studies of LPFC sulcal patterning45, we hypothesized a relationship between the depth of tertiary sulci and reasoning performance.To address this gap in knowledge, we characterized LPFC tertiary sulci in a developmental sample. We studied a broad age range—children and adolescents between 6 and 18 years old—as we sought to leverage the neuroanatomical and cognitive variability intrinsically present in the sample in order to explore whether variability in tertiary sulcal morphology explains individual and developmental variability in relational reasoning. As sulcal depth is a characteristic feature of tertiary sulci, which are shallower than primary and secondary sulci26 with data-driven analyses to model sulcal morphological features and reasoning performance. We report three main findings. First, in our developmental sample, LPFC tertiary sulci can be reliably identified and are smaller, shallower, and more variable compared to primary LPFC sulci as in adults26. Second, there is a relationship between LPFC tertiary sulcal depth and reasoning performance across individuals such that a predictive model accurately captures the relationship between an individual’s LPFC tertiary sulcal depth and reasoning score above and beyond age in an independent sample. Third, this neuroanatomical-behavioral model does not generalize to other sulcal features or cognitive tasks. These findings quantitatively link LPFC tertiary sulcal morphology and reasoning performance, as well as provide cognitive insights from evolutionary new brain structures in LPFC.In this work, we developed a pipeline Fig.  that comN = 33) and Replication (N = 28) samples with comparable age distributions (Discovery: mean(sd) = 12.0 (3.70); Replication: mean(sd) = 12.32 (3.53); p = 0.81). For each participant, we generated cortical surface reconstructions in FreeSurfer67 from high-resolution T1-weighted anatomical scans. As current automated methods do not define LPFC tertiary sulci and often include gyral components in sulcal definitions  and the two components of the para-intermediate frontal sulcus . We defined sulci on the inflated and pial cortical surfaces of each hemisphere for each participant (“Methods”). We emphasize that 1320 manual labels were created in total to examine the relationship between LPFC sulcal depth and reasoning performance , anteriorly by the horizontal (imfs-h), and ventral (imfs-v) components of the intermediate frontal sulcus, superiorly by the two components of the superior frontal sulcus (sfs-p and sfs-a), and inferiorly by the inferior frontal sulcus (ifs). Throughout the paper, we refer to this region as the LPFC Fig. . Studiesr = 0.84, p < 0.0001).All primary sulci—the central sulcus (cs), the superior (sprs) and inferior (iprs) portions of the precentral sulcus, as well as the sfs-p, sfs-a, ifs, imfs-h, and imfs-v—were identifiable in both hemispheres of each individual participant. We demonstrate that tertiary sulci in LPFC are consistently identifiable within the hemispheres of participants as young as 6 years old Fig. . The thrr = 0.70, left hemisphere: r = 0.79, all ps < 0.0001) and these were also consistent between hemispheres in this sample , which assures that all repeated-measures statistics are balanced for effects of sulcus and hemisphere.45, and recent in vivo studies in adults show that LPFC tertiary sulci are in fact significantly shallower and more variable than primary sulci in adults25. However, this correspondence has not been established for LPFC sulci in children and adolescents. Thus, we next sought to compare the depth and variability of LPFC tertiary and primary sulci in 6–18 year-olds. Sulcal depth was normalized to the maximum depth value within each individual hemisphere in order to account for differences in brain size across individuals and hemispheres (“Methods”). From these normalized measures, we conducted a two-way repeated-measures analysis of variance (rm-ANOVA) to statistically test for differences between sulcal type  and hemisphere  in both Discovery and Replication samples.Classic anatomical studies report a high correspondence between sulcal classification and depth25, we observed a main effect of sulcal type  = 95.63, p < 10−3, η2G = 0.35) in which tertiary sulci were significantly more shallow than primary sulci (Mean(sd)Tertiary = 0.04(0.17); Mean(sd)Primary = 0.23(0.07)). We also observed an interaction between sulcal type and hemisphere  = 5.67, p < 0.02, η2G = 0.01) in which tertiary sulci were significantly deeper in the right hemisphere than in the left hemisphere (Mean(sd)RH = 0.06(0.17); Mean(sd)LH = 0.02(0.1)). In contrast, the depth of primary sulci did not differ between hemispheres (Mean(sd)RH = 0.21(0.07); Mean(sd)LH = 0.23(0.07)); Fig. p < 10−3, η2G = 0.43), with no differences between hemispheres (p = 0.3).Consistent with findings in adultsp < 10−3, η2G = 0.46; Mean(sd)Tertiary = 0.02(0.16); Mean(sd)Primary = 0.23(0.07)). We did not observe an interaction with hemisphere in this sample  = 0.26, p = 0.62); Fig. p < 10−3, η2G = 0.47).We observed the same main effect of sulcal type in the Replication sample. Tertiary sulci were more shallow than primary sulci  = 136.5, r = 0.58, p < 10−3) and Replication samples , there was an inconsistent relationship between sulcal depth and age in either sample . First, we implemented a feature selection technique in the Discovery sample  or Matrix reasoning (p = 0.51); therefore, we do not consider gender further in our models.To examine the relationship between LPFC sulcal depth and reasoning scores, we implemented a data-driven pipeline with an emphasis on producing reliable and generalizable results. Based on current gold-standard recommendationsple Fig.  to deterα)69, we iteratively fit the model with a range of α-values using cross-validation. By convention69, we selected the α that minimized the cross-validated mean-squared error , highly associated with reasoning  was highly associated with reasoning score in the Replication sample . In addition, we observed a high correspondence (Spearman’s rho = 0.70) between predicted and actual measured reasoning scores , the predictions of reasoning performance and model fits improved even further in the Replication sample , indicating that the depths of these right hemisphere tertiary sulci identified by our model-based approach explained a unique amount of variance in reasoning scores above and beyond age . The bootstrapped CIMSE showed that this model also suffered from very high variance  age alone or (2) sulcal depth from all right hemisphere LPFC sulci and age together in the Replication sample Fig. . This neage Fig. . In addince Fig. . Taken t73 and (2) a model in which we replaced reasoning performance with performance on a behavioral measure that reflects a general cognitive ability: processing speed74. We used the Akaike Information Criterion (AIC) to quantitatively compare models. If the ∆AIC is >2, it suggests an interpretable difference between models. If the ∆AIC is >10, it suggests a strong difference between models, with the lower AIC value indicating the preferred model76 (“Methods”).Finally, while our data demonstrate support for our hypothesis, we wondered whether our findings extended to other neuroanatomical features or related measures of cognitive development. We repeated our procedure with (1) a model in which we replaced sulcal depth with cortical thicknessR2CV = 0.33; MSECV = 13.54), but much less than the model with age alone . The AIC for the thickness + age model (AICThickness = 78.58) was much higher than the AIC for the tertiary sulci + age model . This indicates that sulcal depth is strongly preferred as a predictor over cortical thickness  and age was associated with processing speed , but not much more than age alone . The AIC for the processing speed + age model (AICCrossOut = 89.59) was much higher than the AIC for the tertiary sulci + age model , which indicates that reasoning is strongly preferred over processing speed .To further probe the relationship between these sulci and reasoning, we performed a follow-up analysis with a measure of phonological working memory (Digit Span Forwards) as another point of comparison. Like processing speed, working memory is a general cognitive ability that is correlated with—and theorized to support—reasoning25 across all participants with at least one identifiable pimfs component in each hemisphere (N = 58). We provide examples of the unthresholded probability maps, which capture the spatial variability across participants, as well as maps thresholded at 20 and 33% overlap across participants . These probability maps can be projected to cortical surfaces in individual participants across ages , we sought to generate spatial probability maps that can be shared with the field. The benefit of such maps is that they capture both the stable and variable features of LPFC sulci across participants. We calculated probability mapsnts Fig. . Threshoges Fig.  and can 79. A consistent finding from these previous studies is that developmentally and evolutionarily meaningful changes in sulcal morphology are not homogeneous within association cortices; instead, such changes are focal and related to different aspects of neuroanatomical and functional networks that are behaviorally meaningful83. After manually defining 1320 sulci in individual participants and implementing a data-driven approach with nested cross-validation in both Discovery and Replication samples, our results are consistent with and extend these previous findings by showing that the sulcal depth of particular LPFC tertiary sulci are linked to behavioral performance on a reasoning task in a developmental cohort, above and beyond age. In the sections below, we discuss (1) the identification of tertiary sulci in future studies, (2) potential underlying mechanisms that likely contribute to the relationship between tertiary sulcal depth and cognitive performance, (3) how the present findings provide a foundation for future studies attempting to link the morphology of brain structures to behavior and functional brain representations, and (4) how our model-based approach can be applied to study other association cortices across the lifespan.Recent studies examining sulcal morphology in humans and other species continue to improve our understanding of the development and evolution of association cortices. They also provide anatomical insights into cognitive skills that set humans apart from other species30, while the paracingulate sulcus is only identifiable in ~70% of hemispheres with a left hemisphere bias in medial prefrontal cortex in humans46 and only ~30% of the time in chimpanzees with no left hemisphere bias20. Consistent with recent findings in adult LPFC25, we could identify all three pmfs sulcal components in each hemisphere across participants in our developmental cohort. On the other hand, we could identify the pimfs components in a majority of participants, but not all. Thus, our findings are consistent with the previous literature regarding the definitions of tertiary sulci in different lobes. For instance, beyond LPFC and VTC, Lopez-Persem and colleagues46 found that some ventromedial PFC tertiary sulci are consistently identifiable, while other tertiary sulci are more variable. This is in line with our findings in LPFC—that the pmfs-p, pmfs-i, and pmfs-a are present in all participants, whereas the pimfs is variable in its presence and number of components.While it may seem surprising that we were able to identify each pmfs component in every hemisphere, our findings are consistent with previous work showing that some tertiary sulci are identifiable in every hemisphere and others are not. For example, the mid-fusiform sulcus in ventral temporal cortex (VTC) is identifiable in every hemisphere in humans and non-human hominoids84 with a classic theory9 and propose a hypothesis linking sulcal depth to short-range anatomical connections, and in turn, to cortical networks and cognitive performance. Specifically, in the 1960s, Sanides28 proposed that morphological changes in tertiary sulci would likely be associated with the development of higher-order processing and cognitive skills. The logic of Sanides’ hypothesis extends from the fact that tertiary sulci emerge last in gestation and have a protracted development after birth, while complex cognitive skills such as reasoning ability also have a protracted development in childhood. Our findings support this classic hypothesis. However, while the LPFC is considered critical to reasoning41, reasoning performance cannot be localized to a single structure85 and thus, the mechanism behind this relationship still needs to be investigated.An immediate question generated from our finding is Why might sulcal depth help to explain children and adolescents’ performance on a cognitive task, above and beyond age? We offer one potential explanation that integrates recent anatomical findings28, which is critical for short- and long-range connectivity, as well as the efficiency of communicating neural signals among regions within cortical networks86. Second, anatomical work in non-human primates has shown that long-range white matter fiber tracts have a bias for terminating in gyri, while additional short-range white matter fibers commonly project from the deepest points (fundi) of sulci84, which we refer to as fundal fibers. These previous and present findings serve as the foundation for the following mechanistic hypothesis linking tertiary sulcal depth to anatomical connections and neural efficiency: deeper tertiary sulci likely reflect shorter fundal fibers, which in turn, reduce the length of short-range anatomical connections between cortical regions, and thus, increase neural efficiency. While speculative, this hypothesis is similar in logic to the tension-based theory of cortical folding87 and also feasible given the fact that short-range structural connectivity increases and sulci deepen during development89. This increase in neural efficiency could underlie variability in cognitive performance, which can be tested in future studies incorporating anatomical, functional, and behavioral measures, as well as computational modeling.As a starting point toward understanding the underlying mechanism, two recent empirical findings provide underlying anatomical mechanisms that could support this relationship between tertiary sulci and cognition. First, there is a relationship between human LPFC tertiary sulcal morphology and myelination73. While we find an association between reasoning and cortical thickness, when considering individual tertiary sulci, our analyses indicate that the depths of tertiary sulci and age together are much stronger predictors of reasoning than the cortical thickness of these sulci and age together. In fact, when including the cortical thickness of sulci in the model, performance was not better than age alone . Thus, future studies exploring the relationship between sulcal morphology and behavioral performance in additional cognitive tasks at the level of individual participants will begin to generate a more comprehensive sulcal-behavioral map in LPFC with additional insights into cortical networks.We also clarify that the present approach of precise anatomical mapping of tertiary sulci does not imply that reasoning can be localized to a single sulcus, or even a single cortical region. In fact, our previous work, including previous studies on this dataset, has focused extensively on the distributed nature of reasoning, highlighting patterns of functional and structural connectivity between prefrontal and parietal regions that support this process65 and variability in sulcal morphology in the medial prefrontal cortex has been associated with changes in cortical morphometry linked to individual differences in cognitive performance and clinical symptom presentation in patients with schizophrenia20. In addition, in LPFC, Miller and colleagues25 showed that the different pmfs components explored here were functionally distinct in adults with respect to resting-state connectivity profiles. In terms of the latter, numerous functional neuroimaging studies show that LPFC is central for reasoning performance90. More explicitly, several studies also indicate that the middle frontal gyrus, the gyrus in which the three sulci  identified by our model are located, plays an important role in cognitive processes that are integral for reasoning, such as maintaining representations and forming associations4. Thus, future investigations of functional connectivity, as well as functional representations, relative to tertiary sulci in future studies in children and adults will likely bring us closer to understanding the complex relationship between the development of LPFC anatomical organization, functional organization, and behavior.In addition to this sulcal-behavioral map in LPFC, two recent lines of work show feasibility for future studies attempting to link tertiary sulcal morphology to brain function, especially for functional activity related to reasoning: one related to tertiary sulci as a meso-scale link between microstructural and functional properties of LPFC and the other identifying functional representations related to reasoning. In terms of the former, a series of recent studies have shown that tertiary sulci are critical functional landmarks in different association cortices91, and also contains tertiary sulci26. In addition, structural connectivity between frontal and parietal regions increases across development93. Thus, future studies can explore how morphological features of tertiary sulci in (a) LPFC and lateral parietal cortex contribute to reasoning performance and (b) different association cortices contribute to performance on cognitive tasks, as well as functional representations in each cortical expanse. It will also be important to explore the relationship among tertiary sulci across cortical regions. For example, developmental studies are well suited to explore how the variability in sulcal morphology in one cortical region, such as LPFC, might affect morphology of tertiary sulci in other cortical regions, such as medial frontal or parietal regions. Our modeling approach can also be applied to data across the lifespan—either cross-sectionally or longitudinally. While it is known that tertiary sulci are shallow indentations in cortex that emerge last in gestation (relative to primary and secondary sulci), and have a protracted development after birth45, the history of LPFC sulcal definitions, especially within the MFG, has been contentious28. Thus, while we used these classic studies to guide the labeling of each sulcus, the distinctions among primary, secondary, and tertiary sulci should be confirmed by modern studies of cortical folding in gestation. Crucially, our findings are not dependent on this classification. Our data-driven, model-based approach identified that a subset of shallow sulci in LPFC explains the most variance in reasoning scores across participants above and beyond age in both Discovery and Replication samples. In addition, the developmental timeline of tertiary sulci relative to the development of functional representations and cognitive skills is unknown. Future studies implementing and improving our model-based approach can begin to fill in these gaps in the developmental timeline of tertiary sulci anatomically, behaviorally, and functionally.While we limit our focus to the LPFC in the present study, both because of its relevance for reasoning, but also because of the immense manual labor involved in this type of study, the data-driven pipeline introduced here can be applied to any cortical expanse. For example, lateral parietal cortex is also critical for relational reasoning, is expanded in humans compared to non-human primates94 and we had a large N (>1000) in terms of sulci explored in the present study, new methods and tools will need to be developed to increase the number of participants in futures studies. Increasing the number of participants will improve the diversity of our sample and reduce imbalances in gender or other demographic features  and Replication  samples. For the Discovery sample, 33 typically developing individuals between the ages of 6–18 were randomly selected from the Neurodevelopment of Reasoning Ability (NORA) dataset44. Demographic and socioeconomic data are summarized in Supplementary Table The present study consisted of Discovery  were acquired for cortical morphometric analyses.n = 28, Replication: n = 27). Reasoning performance was measured as a total raw score from the WISC-IV Matrix reasoning task96  was assessed from raw Digit Span Forward scores (Replication: Mean(sd) = 9.03(1.77)). Digit Span Forward scores measure WM maintenance and attention. For each forward trial, participants were presented with a string of numbers by the experimenter and were asked to immediately repeat the numbers in the same order. The task consisted of eight questions with two trials per level . Each question  consisted of a longer string of numbers than the question before. Both processing speed and working memory were selected as they are considered related, but separable, measures from reasoning. We report the Spearman correlation coefficient (rho) among each of the three behavioral measures in Supplementary Fig. 67 (FreeSurfer 6.0.0) were used to generate cortical surface reconstructions. Each anatomical T1-weighted image was segmented to separate gray from white matter, and the resulting boundary was used to reconstruct the cortical surface for each participant100. Each reconstruction was visually inspected for segmentation errors, and these were manually corrected when necessary. Tertiary sulci are easier to identify on T1 images and cortical surface reconstructions compared to post-mortem tissue (see the “Introduction”) for two main reasons. First, T1 MRI protocols are not ideal for imaging vasculature; thus, the vessels that typically obscure the tertiary sulcal patterning in post-mortem brains are not imaged on standard resolution T1 MRI scans. Indeed, indentations produced by these smaller vessels that obscure the tertiary sulcal patterning are visible in freely available datasets acquired at high field (7T) and micron resolution (100–250 μm)102. Thus, the present resolution of our T1s (1 mm isotropic) is sufficient to detect the shallow indentations of tertiary sulci, but is not confounded by smaller indentations produced by vasculature. Second, cortical surface reconstructions are made from the boundary between gray and white matter; unlike the outer surface, this inner surface is not obstructed by veins and arteries29.All T1-weighted images were visually inspected for scanner artifacts. FreeSurfer’s automated segmentation tools26. This atlas offers a comprehensive schematization of sulcal patterns in the cerebral cortex. The LPFC definitions have recently been validated in adults25, but to our knowledge, these sulci have never been defined in a developmental sample. 12 LPFC sulci were manually defined within each individual hemisphere in tksurfer25 . Briefly, depth values are calculated based on how far removed a vertex is from what is referred to as a “mid-surface,” which is determined computationally so that the mean of the displacements around this “mid-surface” is zero. Thus, generally, gyri have negative values, while sulci have positive values. Given the shallowness and variability in the depth of LPFC tertiary sulci, some mean depth values extend below zero. We emphasize that this just reflects the metric implemented in FreeSurfer. For example, max depth values are above zero for all sulci  the anterior and posterior components of the superior frontal sulcus (sfs) served as the superior boundary, (2) the inferior frontal sulcus (ifs) served as the inferior boundary, (3) the central sulcus served as the posterior boundary, and (4) the vertical and horizontal components of the intermediate frontomarginal sulcus (imfs) served as the anterior boundary. We also considered the following tertiary sulci: anterior (pmfs-a), intermediate (pmfs-i), and posterior (pmfs-p) components of the posterior middle frontal sulcus (pmfs), and the para-intermediate frontal sulcus (pimfs)26. Please refer to Fig. Sulci were manually defined separately in the Discovery and Replication samples according to the most recent atlas proposed by Petrides66.While we could not identify the dorsal and ventral components of the pimfs in every hemisphere , relative to the total frequency of occurrence of that sulcus in the hemisphere Fig. . We repo25. These maps were generated across all participants with at least one pimfs component in each hemisphere. To generate the maps, each label was transformed from each individual to the common fsaverage space. We chose to use the standard fsaverage template to increase accessibility for future studies. Then, for each vertex, we calculated the proportion of participants for whom that vertex is labeled as the given sulcus. In the case of multiple labels, labels were assigned to each vertex with a “winner-take-all” approach. That is, the sulcus with the highest overlap across participants was assigned to a given vertex. Consistent with Miller et al.25, in addition to providing unthresholded maps, we also constrained these maps to be maximum probability maps (MPMs), which helps avoid overlapping sulci and can increase interpretability  were computed in native space from the .sulc file generated in FreeSurfer 6.0.066. We normalized sulcal depth to the maximum depth value within each individual hemisphere in order to account for differences in brain size across individuals and hemispheres. All depth analyses were conducted for normalized mean sulcal depth. As cortical thickness is a commonly used metric in developmental studies, we also considered the mean cortical thickness (mm) for each sulcus. Mean cortical thickness for each sulcal label was extracted using the mris_anatomical_stats function that is included in FreeSurfer67.As the most salient morphological feature of tertiary sulci is their shallowness compared to primary and secondary sulci27 . Previous research identifies the cs, prs, sfs, and ifs as primary sulci. As such, we apply these definitions to the subcomponents of the sfs (sfs-a and sfs-p) and prs (sprs and iprs) considered here.Tertiary sulci are defined as the last sulci to emerge in gestation after the larger and deeper primary and secondary sulci27 Fig. . Specifi26. When considering classic papers and atlases27, both the imfs-h and imfs-v appear to be prevalent prior to 32 weeks, which would define them as primary sulci. Yet, additional studies define sulci in this cortical expanse as secondary15. For the present study, we consider the imfs-h and imfs-v as primary sulci, but it is possible that future studies will establish them as secondary sulci. Critically, our data-driven approach—and in turn, our findings—are agnostic to these distinctions. That is, the model-based approach adopted here quantitatively determines which sulci are most strongly associated with reasoning scores, regardless of their classification. Finally, while historical analyses have not considered modern definitions of pmfs and pimfs sulcal components, more recent studies from Petrides and colleagues do. Moreover, these studies show a correspondence between LPFC tertiary sulcal definitions and brain activation profiles. For example, Amiez and Petrides56 showed that the pimfs and pmfs-a co-localize with clusters of fMRI activation with distinct functional profiles on a serial order memory task. Consistent with this work, Champod and Petrides104 also show a direct relationship between activation profiles and tertiary sulcal patterning within LPFC. Considering these data, we refer to pmfs and pimfs sulcal components as tertiary sulci—for two main reasons. First, from our historical analyses, sulci within the middle frontal gyrus emerge during late stages in gestation, consistent with definitions of tertiary sulci21. Second, from our previous analyses in adults25, pmfs sulcal components are small and shallow relative to other primary and secondary LPFC sulci, which is consistent with morphological features of tertiary sulci. Taken together, our distinction among primary and tertiary sulci is based on classic and modern data. Future studies with larger sample sizes using non-invasive fetal imaging will re-visit the timestamps for the documented sulci, as well as provide new timestamps for those sulci that were not included in these classic studies. For example, based on these classic definitions of sulcal types, the present study did not include any secondary sulci in LPFC. Nevertheless, we also highlight that our data-driven approach is blind to these definitions and identifies sulci that are small in surface area and shallow in depth, which is consistent with the definition of tertiary sulci.Apart from these sulci, the question of whether or not other LPFC sulci should be considered secondary or tertiary is still unresolved. For example, the imfs-v and imfs-h are contemporary labels for classic definitions of sulci commonly labeled as either the frontomarginal and/or middle frontal sulciaov function, imported in python via rpy2. Effect sizes are reported with the generalized eta-squared (η2) metric.We compared sulcal depth of tertiary and primary sulci with a two-way  repeated-measures analysis of variance  as part of our model-selection approach. Not only does this provide a data-driven method for model selection, but regularization techniques are recommended to improve the generalizability of a modelCross-validation: In addition to using regularization techniques to improve generalizability, all models were fit with cross-validation. The purpose of cross-validation is to test the generalizability of a model within a sample. We report a very strong fit for our cross-validated models.Replication in an additional sample: We demonstrate the generalizability of our findings by showing that the depths of sulci that are associated with reasoning in the Discovery sample generalize to the Replication sample. Our regularized regression reveals that the depths of a subset of RH tertiary sulci are relevant for reasoning performance in the Discovery sample Fig. . We thenBootstrapped error estimates: We used bootstrapping as a diagnostic tool to assess the generalizability of our models to out-of-sample data. Using 10,000 iterations, we show our chosen models have low variance in estimated error Fig. , suggestBased on current recommendationsα), to the absolute magnitude of the coefficients such that:We applied a least absolute shrinkage and selection operator (LASSO) regression model to determine which sulci, if any, were associated with Matrix reasoning. The depth of all 12 LPFC sulci was included as predictors in the regression model. LASSO performs L1 regularization by applying a penalty, or shrinking parameter . We used the SciKit-learn GridSearchCV package105 to perform an exhaustive search across a range of α-values (0.01–10.0), and selected the value that minimized cross-validated mean-squared error (MSECV).In a LASSO regression, low coefficients are set to zero and eliminated from the model. In this way, LASSO can facilitate variable selection, leading to simplified models with increased interpretability and prediction accuracyTo further characterize the relationship between sulcal depth and reasoning performance, we used the predictors identified by the LASSO regression in the Discovery sample to predict Matrix reasoning score in the Replication Sample. As age is correlated with Matrix reasoning score, we included age as an additional covariate in the model (1). We fit this model as well as alternate nested models with leave-one-out cross-validation (looCV). We used nested model comparison to assess the unique variance explained by sulcal depth, while accounting for age-related effects on reasoning:In addition, we conducted this analysis with only the two most strongly associated sulci  from the Discovery sample:CV of this model to the MSECV of a model with age as the sole predictor (3):To assess the unique variance explained by tertiary sulcal depth, we compared the MSEx2…x12 represent the sulcal depth of each identified sulcus within a hemisphere.As these models are nested  are also included in the larger models (1), (2)), we are able to directly compare the prediction error in these two models. Finally, to assess the specificity of the relationship to tertiary sulci in our Replication sample, we assessed the fit of model (1) to a full model that included all identified LPFC sulci within a hemisphere (4). The full model is as follows:n = 27) of the Replication sample makes looCV suitable. However, models that are fit with looCV can have high variance. Thus, to assess the potential variance in our estimations, we performed a bootstrapping procedure to empirically estimate the distribution of possible MSEcv predictions for models 1, 2, 3, and 4. For each model, data were randomly selected with replacement 10,000 times and MSEcv was computed for each iteration. From this process, we estimate Median MSE and 95% confidence intervals for each model , which provides an estimate of in-sample prediction error and is suitable for non-nested model comparison. AIC is given by:Li is the likelihood for the model (i) and Ki is the number of parameters. By comparing AIC scores, we are able to assess the relative performance of the two models. If the ∆AIC is >2, it suggests an interpretable difference between models. If the ∆AIC is >10, it suggests a strong difference between models, with the lower AIC value indicating the preferred model76.To assess whether our findings generalized to other anatomical features, we considered cortical thickness, which is an anatomical feature commonly explored in developmental cognitive neuroscience studies99, we investigated the generalizability of the sulcal-behavior relationship to two other widely used measures of cognitive functioning: Processing speed and working memory. Specifically, we used looCV to predict processing speed (as indexed by Cross Out score) and working memory (as indexed by Digit Span Forwards score)108 instead of Matrix Reasoning score. In the cases in which the model showed a strong association, we used AIC to compare the model predictions to Matrix reasoning predictions.To ascertain whether the relationship between sulcal depth and cognition is specific to reasoning performance, or transferable to other general measures of cognitive processingFurther information on research design is available in the Editor Summary.Supplementary Information.Reporting Summary.