ABSTRACT
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 trade-off. 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 65nm CMOS and achieved a 0.227µJ/class energy efficiency in a compact area of 0.014mm2/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 µECoG 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.
ABSTRACT
Optogenetic technologies have been the subject of great excitement within the scientific community for their ability to demystify complex neurophysiological pathways in the central (CNS) and peripheral nervous systems (PNS). The excitement surrounding optogenetics has also extended to the clinic with a trial for ChR2 in the treatment of retinitis pigmentosa currently underway and additional trials anticipated for the near future. In this work, we identify the cause of loss-of-expression in response to transdermal illumination of an optogenetically active peroneal nerve following an anterior compartment (AC) injection of AAV6-hSyn-ChR2(H134R) with and without a fluorescent reporter. Using Sprague Dawley Rag2-/- rats and appropriate controls, we discover optogenetic loss-of-expression is chiefly elicited by ChR2-mediated immunogenicity in the spinal cord, resulting in both CNS motor neuron death and ipsilateral muscle atrophy in both low and high Adeno-Associated Virus (AAV) dosages. We further employ pharmacological immunosuppression using a slow-release tacrolimus pellet to demonstrate sustained transdermal optogenetic expression up to 12 weeks. These results suggest that all dosages of AAV-mediated optogenetic expression within the PNS may be unsafe. Clinical optogenetics for both PNS and CNS applications should take extreme caution when employing opsins to treat disease and may require concurrent immunosuppression. Future work in optogenetics should focus on designing opsins with lesser immunogenicity.
