Closed-loop neural interfaces with on-chip machine learning can detect and suppress disease symptoms in neurological disorders or restore lost functions in paralyzed patients. While high-density neural recording can provide rich neural activity information for accurate disease-state detection, existing systems have low channel counts and poor scalability, which could limit their therapeutic efficacy. This work presents a highly scalable and versatile closed-loop neural interface SoC that can overcome these limitations. A 256-channel time-division multiplexed (TDM) front end with a two-step fast-settling mixed-signal DC servo loop (DSL) is proposed to record high-spatial-resolution neural activity and perform channel-selective brain-state inference. A tree-structured neural network (NeuralTree) classification processor extracts a rich set of neural biomarkers in a patient-and disease-specific manner. Trained with an energy-aware learning algorithm, the NeuralTree classifier detects the symptoms of underlying disorders (e.g., epilepsy and movement disorders) at an optimal energy-accuracy tradeoff. A 16-channel high-voltage (HV) compliant neurostimulator closes the therapeutic loop by delivering charge-balanced biphasic current pulses to the brain. The proposed SoC was fabricated in 65-nm CMOS and achieved a 0.227-mu J/class energy efficiency in a compact area of 0.014 mm(2)/channel. The SoC was extensively verified on human electroencephalography (EEG) and intracranial EEG (iEEG) epilepsy datasets, obtaining 95.6%/94% sensitivity and 96.8%/96.9% specificity, respectively. In vivo neural recordings using soft mu ECoG arrays and multi-domain biomarker extraction were further performed on a rat model of epilepsy. In addition, for the first time in literature, on-chip classification of rest-state tremor in Parkinson's disease (PD) from human local field potentials (LFPs) was demonstrated.