In Blood Oxygenation Level Dependent (BOLD) contrasts fMRI, the most commonly used sequences, gradient echo (GRE) and spin echo (SE), have been challenged due to their limited spatial specificity or functional sensitivity^1,2. As an alternative, an asymmetric spin echo (ASE) sequence was introduced^3,4, yet, its characteristics in different conditions are still unclear. In this study, we have performed simulations and in-vivo experiments to design the optimal ASE pulse sequence that maximizes functional sensitivity while preserving high spatial specificity. The results indicate that ASE pulse sequences can be effectively optimized by modulating T2- and T2'-weighting at 3.0 T and that the optimized ASE pulse sequence can provide enhanced functional sensitivity over the conventional GRE and SE and efficiently improve tSNR and functional activation particularly in regions with high susceptibility field gradients (SFGs). Pulse sequence Figure 1 illustrates the ASE pulse sequence diagram with a spiral-out readout, showing transverse magnetization, M(t), and BOLD contrast, B(t), in different time periods. Hahn-echo Time (TH) is defined as twice the time between 90° excitation pulse and 180° refocusing pulse, and Echoshift as a time shifted away from TH. The three timing parameters, TE, TH, and Echoshift, determine the degree of T2 and T2' weighting associated as TE = TH + Echoshift. Functional Tasks 16 healthy subjects participated in this study. The sensory task consists of visual and auditory stimulation alternating "on" and "off" blocks every 15 seconds. Breath hold tasks consist of repetitions of 20 seconds of normal breathing and 10 seconds of breath hold. fMRI Acquisition fMRI images were acquired on a 3.0 T GE whole-body scanner with an 8-channel head coil using a conventional GRE sequence and the ASE sequence with TR = 2000 ms, TE = 30 ms in the GRE and 65 ms in the ASE, Echoshift = -50, -40, -30, -20, -10, 0, +10 ms, 128 temporal frames, and FOV = 240 × 240 mm. Variable density spiral was applied to enhance the resolution of the matrix size 128×128 from the actual matrix size 110 × 110, and a high-order shimming procedure was used to reduce B0 inhomogeneity prior to the functional scans. Air-inflation sponges were padded on both ears and forehead to inhibit major head motions. fMRI Data Analysis Functional images were analyzed using custom C and MatLab routines aiming to find the correlation between a sinusoidal function and a hemodynamic response depending on functional tasks in voxel-wise temporal frames discarding the first 3 temporal frames. tSNR and t-score maps were utilized for qualitative and quantitative assessment. Optimizing ASE pulse sequences The ASE pulse sequences were optimized by manipulating the timing parameters, TE and Echoshift. Taking into account the dynamics of intrinsic properties of tissue and blood vessels at 3.0 T, TE can be lengthened to 65 ms or even longer in the ASE pulse sequence, so that the ASE is highly sensitive in T2 weighting containing intra-vascular components. Moreover, we have discovered that Echoshift has to be negative (TE < TH). Although the BOLD contrasts at Echoshift = ± 10 ms are almost equal as marked in Figure 2, the entire spiral-out readout windows are placed in a rephasing state with negative Echoshift and in a dephasing state with positive Echoshift resulting in increase and decrease of M(t) and B(t). Therefore, the activation maps in Figure 3 appear T2 and T2* weighted depending on the sign of Echoshift. ASE BOLD contrast Figure 3 & 4 show qualitative and quantitative features of ASE BOLD contrasts. The ASE with large T2' weighting (Echoshift < -30 ms) performs better than or equivalent to GRE, and the ASE with small T2' weighting (Echoshift > -30 ms) performs better than the SE (Echoshift = 0). In BH tasks, however, the ASE is led by GRE in functional activation, indicating that large vessels affect the broader regions. In SFGs regions, the ASE with negative Echoshift is remarkably advanced on GRE attaining 80% tSNR recovery and up to 5.1% functional activation. The ASE pulse sequence can be effectively optimized for BOLD fMRI study at 3.0 T in the range of Echoshift between -50ms and -30ms and achieve improved functional sensitivity particularly in SFGs regions.