A protocol for assessing the effects of treatment on the function of brain networks implicated in cognitive impairment in schizophrenia and ADHD

In both schizophrenia and in ADHD, cognitive impairments are seriously disabling yet current treatments are not adequate. In schizophrenia, current treatments have limited effect, while in ADHD the main concerns are adverse side-effects and limited long term benefits. In both conditions, the cognitive impairments appear to arise from poor coordination of activity in networks of neurons linking widespread brain regions.

The chemical messenger molecule glutamate plays a key role in delivering the information carried by long range neural fibres between remote brain regions, while another messenger molecule, GABA, acts locally to fine-tune the message. Pharmacological agents that modulate glutamate and/or GABA may therefore enhance cognitive function in conditions such as schizophrenia and ADHD in which these networks are disrupted. However, progress has been slow, partly due to lack of good techniques for testing drugs at an early stage of development, and partly because efficient network connectivity is not simply a matter of neurotransmitter levels. The brain's plasticity means that that the networks are sculpted by use, and pharmacological correction of neurotransmitter levels alone may be inadequate to restore function unless it is also accompanied by cognitive training designed to re-sculpt the abnormal networks. Psychiatrist and neuroscientist John H Krystal has invoked the analogy of fitting a horse shoe: drug treatment is like heating the metal to make it malleable, while training is the process of hammering it into shape. Neither alone is likely to produce a well fitting shoe. Therapy that combines pharmacological correction of neurotransmitter abnormalities with cognitive training programs designed to sculpt healthy network connections may hold considerably more promise than either strategy alone.

We will use a novel treatment-testing procedure that combines ultra-high-field Magnetic Resonance Spectroscopy (MRS), which can measure levels of glutamate, GABA and other related molecules at specified regions of the brain, with Magnetoencephalography (MEG), which can measure the amount of neural electrical activity between nodes of the brain networks that support cognitive performance. Using the internet, we will recruit healthy volunteers with traits similar to those of schizophrenia ("schizotypy") and of ADHD, as well as a group of volunteers with low levels of these traits, and record MRS and MEG data, as well as "resting state" fMRI data. Then in the participants with schizotypy and ADHD traits, we will test the effects of a drug that is predicted to enhance cognition by modifying glutamate and GABA signalling in the brain. Half the participants will take the active drug, and half a placebo. We will also ask the volunteers to engage in a cognitive training exercise while MEG scanning is in process, allowing us to measure not only the average effect of the drug, but also any effects of the drug on the way their networks change during learning.

Unlike other MRS techniques, our ultra-high field MRS techniques allow us to distinguish clearly between the various molecules associated with communication between neurons. We have also developed novel procedures for analysing MEG data, which is acquired at closely spaced time points using 275 sensors, giving us high resolution in both time and space, and enabling us to map rapid changes in network activity. In this project, we will refine these techniques and analytical procedures further in order to develop a powerful research tool with which to test potential new treatments for cognitive impairments in mental disorders, particularly those that arise from disruption to long-range brain networks. With this tool, we plan to conduct further research into new treatments for cognitive impairment in mental disorders, particularly those that combine pharmaceutical agents with cognitive training.

Current treatments for cognitive impairments in disorders such as schizophrenia and ADHD are inadequate. The accumulating evidence that these impairments arise from disordered glutamatergic and/or GABAergic transmission within and between distributed cerebral networks suggests that drugs that modulate glutamatergic and/or GABAergic transmission might provide effective treatment. Efficient development of such treatments requires a procedure for measuring the effects of drugs on regional levels of GABA, glutamate (GLU) and its metabolite, glutamine (GLN), and also of measuring the function of the neural networks that support cognition.

We will develop a procedure that employs Magnetic Resonance Spectroscopy (MRS) at 7 Tesla (7T) to measure GABA, GLU and GLN, and a 275 channel MEG system to measure electrical activity in the relevant networks with high temporal and spatial resolution. In comparison with MRS at 3T, at 7T it is possible to clearly distinguish GLU and GLN resonances, while GABA can be measured without the need for J-editing to resolve overlap with other metabolites, thereby allowing measurement of GLU, GLN and GABA in a single spectrum. We have developed MEG analysis techniques, including beamforming and Independent Components Analysis, to measure brain activity in networks, and trial-by-trial supervised linear discriminant analysis for sensitive assessment of change in brain activity over time. Participants will undergo cognitive training during MEG acquisition to test the hypothesis that cognitive training and pharmacological treatment can act synergistically.

We will employ the established antibiotic, minocyline, which has been shown to produce moderate cognitive enhancement in schizophrenia. If this project is successful, we plan to apply this procedure to evaluating other agents such metabotropic glutamatergic modulators and alpha7 nicotinic agonists, in collaboration with academic pharmacologists, and with the pharmaceutical industry.

WHO WILL BENEFIT?

1. Patients with schizophrenia, ADHD and, potentially, people with other disorders associated with cognitive impairment and their carers;
2. Pharmaceutical companies with interest in developing drugs for mental disorders;
3. Mental health professionals involved in the care of patients with schizophrenia and ADHD
4. Educators

TIME SCALE OF IMPACT
We plan to have a deliverable methodology for use by pharmaceutical companies in evaluating new treatments within 2 years.

As both cognitive remediation and cognitive enhancing drugs have already been shown to have small to medium effect sizes in schizophrenia, any findings that the two approaches may work synergistically in schizotypy could be translated into immediate potential benefits to patients and mental health professionals in the form of a recommendation to clinicians to consider combining the two. We would anticipate dissemination of these findings within 1 year of project completion.

The time scale for the development of new successful treatment regimens that might enter into clinical practice is less easy to predict. There is currently a range of pharmaceuticals under investigation for the treatment of cognitive deficits in schizophrenia (see clinicaltrials.gov). Minocycline is currently being investigated in 4 registered trials. Trials of various other novel compounds, including metabotropic glutamate receptor modulators and alpha 7 or alpha4/beta2 nicotinic receptors agonists are in progress. Development of targeted cognitive training programs is likely to follow a similar time course, although it can proceed independently of drug development in the early stages. Benefits to patients, their carers and clinicians and to educators will be felt once the new clinical treatment regimens are translated into regular clinical practice.

HOW WILL THEY BENEFIT?

Patients will benefit from improved cognitive function, and thus greater capacity to take part in the life of society. In the case of ADHD, being a developmental disorder, the research may lead to cognitive training programs that have a preventive role. These benefits will also have impact on patients' carers.

Pharmaceutical companies will be able to confirm the potential efficacy of a novel molecule within a time scale of less than one year after phase 1 trials have established safety, potentially reducing the time it takes to identify a strong candidate treatment by many years, while greatly reducing treatment development costs by reducing the number of unsuccessful phase 3 randomised controlled trials.

Mental health professionals will benefit from improved tools for promoting the welfare of their patients.

Evidence that targeted cognitive training and/or cognitive enhancing drugs may alleviate cognitive impairments could provide teachers with tools with which to address cognitive problems in ADHD in the classroom, and improve the educational progress of their students with ADHD.