Pharmacological Neuroimaging Research

Non-invasive neuroimaging techniques have enabled major advances in our understanding of drug action in the brain. However, neuroimaging techniques provide only indirect readouts of changes in neuronal activity, reflecting blood flow changes in the brain that are related to cellular activity through neurovascular coupling mechanisms, as illustrated below.

Diagram to illustrate neurovascular coupling.

This is problematic for studies of drug action because many neuropharmacological agents themselves have direct vascular or neurovascular effects. As such, it is difficult to differentiate the neuronal, blood flow or combined effects of drug action from neuroimaging signals. See our review papers covering these issues:

  • Haensel JX, Spain A & Martin C (2015) A systematic review of physiological methods in rodent pharmacological MRI studies. Psychopharmacology, 232(3), 489-499.
  • Martin C (2014) Contributions and complexities from the use of in-vivo animal models to improve understanding of human neuroimaging signals.. Frontiers in Neuroscience, 8.
  • Martin C & Sibson NR (2008) Pharmacological MRI in animal models: a useful tool for 5-HT research?. Neuropharmacology, 55, 1038-1047.

Our research in preclinical models combines neuroimaging techniques with other neurophysiological measures of cellular activity to elucidate the neurovascular effects of administered drugs. This work is underpinning our ability to use neuroimaging techniques for drug development research, identifying functional biomarkers, and refinement of our understanding of the neural circuits mediating the actions of neuropharmacological interventions. Current projects include:

1. Neurovascular and neuroimaging effects of hallucinogenic drugs.

In a recent paper we demonstrated that psilocin, the active metabolite of psilocybin which is found in magic mushrooms, is able to alter the relationship between brain blood flow and neuronal activity. This might have important implications for the mechanism of action of this, and similar drugs. Our findings also highlight the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data. A link to this paper (open access) is here. We are now extending this work to include other psychoactive and serotonergic drugs.

2. Effects of cholinergic drugs upon neurovascular function (Gaia Brezzo).

Acetylcholine (ACh), as most neurotransmitters, is a strongly vasoactive substance meaning it is able to directly influence blood vessel tone in addition to having indirect effects on the vasculature via modulation of neuronal activity. Drugs that act to increase brain ACh levels are prescribed to Alzheimer's disease (AD) patients as one of a very few forms of therapy that can provide some temporary relief of cognitive symptoms. Interestingly, dysfunction of brain blood flow regulation and neurovascular function are increasingly being recognised as major drivers of neurodegenerative diseases such as AD. Bringing these insights together, we are currently investigating how drugs that alter brain ACh modulate neurovascular function in order to test the general hypothesis that cholinergic drug efficacy in AD is partly attributable to restorative effects upon cerebral blood flow regulation.

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