Systems and methods for generating stimulation signals for brain or nerve stimulation are disclosed. In one arrangement, a signal generation unit generates a stimulation signal and transmits the stimulation signal to a stimulation unit. The stimulation unit applies the stimulation to a biological system. The stimulation signal is defined by at least one stimulation parameter. A data receiving unit receives time series biomarker data comprising measurement samples representing one or more biomarkers indicative of a condition of the biological system that is affected by applied stimulation based on the stimulation signal. A controller controls generation of the stimulation signal based on the received biomarker data. The controller uses a model of the biological system to estimate an optimal value of the at least one stimulation parameter using the biomarker data. The model defines strengths of contribution of measurement samples to the estimate based on the times at which the measurement samples were obtained.