Control of neuronal networks and cognitive behaviour by deep brain, transcranial and optogenetic stimulation

Your brain is constantly doing sums, weighing-up past experience and the current situation in order to decide how best to behave. Unfortunately, patients with brain diseases like schizophrenia have trouble coping with these decisions that most of us take for granted; electrical activity in different parts of their brains becomes subtly uncoordinated, making it difficult to see the wood for the trees. This project will use stimulation techniques designed to control the brain‘s electrical signalling (very carefully - you wouldn‘t notice if it was done to you) to see if we can re-coordinate brain activity at important times, such as during decisions.
Brain activity during sleep is also important, often mirroring previous events. This reflects the brain ‘sorting out‘ recent thoughts, preparing useful information for long term storage. A bad night‘s sleep is often followed by sluggish thoughts, and sleep is commonly impaired in brain disease. We will therefore also use brain stimulation during sleep to see if that can boost efficient decision-making.
It is difficult to design drugs to treat impaired thought processes. Our research will develop new techniques that - potentially in combination with future drugs - can be used to treat thought disorders in schizophrenia and related diseases.

Learning, memory and decision-making arise through coordinated activity across networks of brain regions that encode, integrate and store information about behavioural parameters including location, reward and rules. The hippocampus and prefrontal cortex are central to such cognitive processes, and constitute an experimentally tractable model system in which to define the neuronal network bases of cognition, its experience-dependent modulation and its impairment in psychiatric diseases including schizophrenia. My own work has shown how coordination of rodent hippocampal-prefrontal activity underlies functional connectivity, selectively enabling information transfer during working memory and decision-making. An analogous framework translates to humans, and appears impaired in schizophrenic patients.

Despite this converging evidence regarding the nature of hippocampal-prefrontal interactions, little is known about control mechanisms: how does input to the two structures modulate their coordination according to current behavioural demands? Can exogenous control of their coordination be used to generate behavioural changes or treat disease symptoms? I will answer these questions using a novel combination of network recordings and neural stimulation techniques that mimic endogenous neurophysiological mechanisms, allowing the entrainment of neuronal activity at key behavioural timepoints and thus direct control of cognition.

Dopaminergic and cholinergic neuromodulatory systems are known to directly influence hippocampal and cortical activities. Using stimulation patterns informed by computational models and analyses, event-related deep-brain stimulation of dopaminergic and cholinergic projections will be used to influence encoding of reward and spatial information during decision-making behaviour.
Complementary optogenetic approaches - with which genetically-defined subsets of dopaminergic, cholinergic and GABAergic cells can be selectively activated with millisecond precision - will enable dissection of the distinct roles of dopaminergic and cholinergic projections and their interactions with inhibitory neurotransmission in hippocampal-cortical networks.
Coordinated neuronal activity during sleep is critical for cognition, and its disruption by abnormal sleep patterns generates or exacerbates cognitive symptoms in a wide range of diseases. Rhythmic deep-brain and transcranial stimulation - mimicking the oscillatory patterns seen during natural sleep - will be used to entrain hippocampal-cortical network activity believed to underlie memory consolidation. In collaboration with Eli Lilly & Co., this manipulation will be used to try and normalise disrupted sleep neurophysiology and behaviour in a rat model of schizophrenia.

This unique combination of state-of-the-art electrophysiological and genetic technologies with behavioural testing and psychiatric disease models will extend understanding of normal and pathological neuronal network activity, and rationalise stimulation protocols that may be used therapeutically to control brain activity and enhance or repair cognitive processing.