Circuit-driven neuromodulation in the cognitive domain

Deep brain stimulation (DBS) is a therapy for brain disorders where electrodes, placed deep in the brain, are used to continuously deliver electrical pulses that interrupt brain activity that causes abnormal movement. DBS has also been used to treat cognitive symptoms of brain disorders, but the results have been inconsistent. Imaging studies suggest cognitive symptoms occur because parts of the brain become too strongly or weakly connected. Delivering continuous electrical pulses, as in current DBS, may not be the best way of returning the strength of these connections to a healthy state. In the healthy brain, connections between groups of brain cells become stronger when they are activated together. We propose to use this principle to find better ways to change the strength of connections between brain areas. To develop these techniques, we will carry out “closed-loop” experiments in rodents, where recordings of brain activity in one area are used to control the timing of stimulation to a connected area. We will test the effectiveness of these approaches by seeing whether they lead to changes in the performance of cognitive tasks. We will carry out our experiments using electronics that allow fast translation of successful approaches to human medical devices

Neuromodulation using deep brain stimulation (DBS) is a highly successful treatment for the motor symptoms of movement disorders. In comparison, DBS treatment for the cognitive symptoms of brain disorders is in its infancy and has been only partially successful. This suggests the current targets for treating cognitive symptoms are viable, but that current stimulation paradigms are suboptimal. Our goal is to establish novel approaches to neuromodulation of current DBS targets that will improve cognitive symptoms in neurological and psychiatric disorders. These approaches will be designed to modulate specific processes in cortico-basal ganglia-thalamocortical circuits that mediate behaviours relevant to several brain disorders. Specifically, we propose that utilising the temporal dynamics of these neural circuits has the potential to have more direct and powerful effects on cognitive symptoms than current methods. Using experiments in rodents, we will use optogenetic and electrical stimulation to manipulate the timing of activity in connected cortical and subcortical areas, utilising their underlying temporal dynamics to strengthen or weaken their connectivity. This “closed-loop” approach will utilise recordings of neuronal signals, including the phase of ongoing local field potential oscillations and spiking activity, in one area of cortico-basal ganglia-thalamic circuits to control the timing of stimulation delivered to one of its target areas. Our approaches will combine expertise in the cell-type specific composition of cortico-basal ganglia microcircuits and the development of novel methods of brain stimulation. We will target behaviours relevant to several neurological and psychiatric diseases, with the rationale that the crucial first step for novel neuromodulation is to uncover approaches that modulate disease-relevant circuits in a way that leads to reproducible behavioural change. To this end, we will quantify the neurophysiological changes elicited by closed-loop stimulation that occur concurrently with alterations in cognitive task performance. Importantly, we will perform closed-loop manipulations using algorithms that run on self-contained programmable chips. This approach will facilitate the translation of closed-loop algorithms to equivalent platforms in the next generation of human stimulation devices and we will explore collaborations with the medical devices industry to facilitate this. In addition to our translational goals, these studies will provide fundamental insights into how the strength of connectivity between different nodes of cortico-basal ganglia-thalamic loops contribute to the performance of specific behaviours.