Temporary connective architectures in mind and brain: role of functional connectivity in working memory

The ability to hold information in mind for short periods of time depends on working memory. Working memory provides the functional backbone to high-level cognition - by holding information in working memory, we are able to perform complex actions based on time-extended goals and contextual contingencies. Put simply, working memory frees action from direct stimulus dependency. This research explores the fundamental neural principles of working memory, and how they contribute to flexible human cognition.

The neuroscience of working memory faces a particular challenge: brain activity is highly dynamic. At first glance these dynamics seem at odds with the very nature of working memory. How can we keep a stable thought in mind while brain activity is constantly changing? Indeed, some of the most influential models in neuroscience are built on the first-level intuition that stability of mind depends on stable brain activity. Classic models assume that working memory is maintained by static patterns of neural activity, as if frozen in time to preserve a still-frame representation of the past. But new methods for measuring and analysing brain activity reveal a much more dynamic portrait: neural activity patterns are constantly changing, even when mental states remain stable.

We need to develop an alternative theory to account for dynamic activity. In this research, we will test a new hypothesis that working memory in maintained by laying down specific, but temporary neural pathways. This idea allows for a more dynamic theory of brain function, but so far remains essentially untested. A region in the frontal lobe, known as prefrontal cortex, has been identified as particularly important for working memory maintenance. The first step in this research is to determine the brain processes that allow neural pathways in this area to adapt as rapidly as thought itself.
Fundamental neurophysiological principles for working memory will be established by analysing a large-scale database of cellular recordings from prefrontal cortex. This international collaborative study will capitalise on more than ten years of research at leading institutions around the world, culminating in a database of unprecedented size to address fundamental questions that have so far been beyond the scope of individual experiments. In parallel, we will also study brain activity measured in patients undergoing pre-surgical neurological monitoring. This provides an exciting opportunity to measure high-level thought processes directly from the human brain. Access to these unique datasets will allow us to analyse how prefrontal networks are configured for working memory by testing how pathways can be flexibility established, and erased, according to changing memory demands. This research will also shed new light on capacity limits in human cognition.

It is often assumed that the capacity to maintain information in working memory limits performance for a broad range of cognitive demands. However, this new research could provide an alternative explanation. Capacity limits may be more closely related to challenges associated with accessing information stored in brain connections. This raises the intriguing suggestion that cognitive capacity limits are not so much constrained by the sheer amount of information that we can keep in mind, but rather how we can put that information to use. Individual differences in memory capacity are strongly coupled to standard measures of general intelligence as well as real-world measures of academic progress and professional success. A deeper understanding of the fundamental neurophysiology mediating this core cognitive function could have broad implications for improving mental capacity in general.

Working memory is a core cognitive function that allows us to hold in mind task-relevant information for short periods of time. According to standard models of working memory, persistent activity patterns in prefrontal cortex represent and maintain mnemonic content. However, we argue that this model does not fit with recent data showing that brain activity is inherently dynamic. Therefore, we propose an alternative theory: working memory is maintained in temporary changes of effective connectivity in prefrontal cortex.
To test this hypothesis, we will explore the role of two mechanisms for effective connectivity: short-term synaptic plasticity (Study 1) and neural coherence (Study 1 & 2).
Short-term synaptic plasticity (STSP) is inferred from changes in synaptic efficacy, which in turn are inferred from statistical dependencies in activity between two simultaneously recorded cells. To attain sufficient statistical power for our first objective, we will exploit a large sample of pre-existing extracellular recordings from monkey prefrontal cortex. To achieve our second objective, we will test the role of neural coherence in maintaining temporary connectivity states for working memory. The analysis in Study 2 will follow a similar approach to Study 1, however using frequency-specific coherence between local populations as the dependent measure.
Finally, we will extend this programme to the human brain via a cohort of clinical patients with intracranial electrodes implanted to monitor seizure activity. This provides a unique opportunity to integrate human and animal models using a common neural signature (i.e., neural coherence). The main objective is to directly translate findings from Study 1 & 2 to human brain and cognition. However, we have also developed a novel task that allows us to test additional predictions generated from our theoretical framework (e.g., whether memory-related coherence patterns code for future goals, rather than past experience per se).

Economic & Societal Impact:
Reduce the burden on animals used in research: Study 1 & 2 will maximise use of pre-existing animal data (with immediate effect). Moreover, integrating experiments in monkey and human will improve understanding of the link between animal and human intracranial data, which could help reduce the demand for future animal research (potential long-term benefit).

Health & well-being: iEEG data will support clinical research to replace invasive procedures with MEG (Voets/Woolrich). This is a major public health goal. Eliminating this invasive neurosurgical procedure (+ weeks of post-surgery monitoring in intensive care) would benefit patients and reduce costs to the NHS. The likely time-scale is difficult to estimate. A significant new advance could benefit patients immediately, however progress is more likely to be incremental, so we are prepared for a longer-term project.

Patients undergoing deep brain stimulation will be assessed for effect of stimulation on task performance (in addition to recording for Study 3). This will be used to test for higher-cognitive side-effects of this relatively new treatment for chronic pain. Again, it is difficult to estimate a time-frame for benefit, but if ill-effects were detected then changes in the protocol would be relatively immediate.

I am also a co-applicant on a large-scale NHS-funded (£2.5m) project to track working memory performance in ageing and dementia (PIs: Nobre; Johansen-Berg). This on-going research also uses complementary imaging modalities, and so methodological developments for this project will directly benefit this applied research in ageing and dementia (within one or two years of the starting the project).

Public engagement: I host a general audience blog, Brain Box, which has received more than 50,000 page views in the first two years (currently ~80 views per day). I use this platform to describe all new research from my lab (first and senior author papers) in accessible language, but also to comment on latest neuroscience stories, and controversies, in the mainstream news. Where appropriate, I also reach a wider audience through newspapers articles, including the Independent and the Guardian, as well as the blog hosted by the generalist journal, Nature [Education section, aimed at high school/undergraduate students]. I will be able to use these routes to help disseminate the results of the proposed research in the public domain. All research output will be summarised in accessible language at The Brain Box, and to mainstream media where appropriate. We will also highlight how this research relates to advances in epilepsy treatment at Oxford's annual Brain Awareness Week.