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23 January 2015

Cantab and its application to Cognitive Toxicity by Prof Trevor Robbins

Virtually all effective drugs are almost bound to have some ‘adverse side-effects’ which can be the product of a drug’s non-specific modes of action, or may simply reflect effects at other receptors distal from the therapeutic target. Professor Trevor Robbins, Senior Consultant at Cambridge Cognition, Professor of Cognitive Neuroscience at University of Cambridge and co-creator of Cantab explores the importance of cognitive safety profiling in clinical trials.

Professor Trevor Robbins

Author: Professor Trevor Robbins, Professor of Cognitive Neuroscience and Head of the Department of Psychology at the University of Cambridge. He is also Director of the Cambridge University MRC-Wellcome Trust funded Behavioural and Clinical Neuroscience Institute (BCNI), the main objective of which is to inter-relate basic and clinical research in psychiatry and neurology.

Key Points: 

  • All effective drugs are almost bound to have some ‘adverse side-effects’ which can be the product of a drug’s non-specific modes of action.
  • Safety with drugs is paramount, especially when the major functions of the brain are threatened.
  • Cantab tests have been shown to be useful for defining the specific network of brain structures responsible for their performance.
  • Clinical Trial Information Systems Profile and Profile 2+ provide accurate measurement of a compound’s effects on cognition and the brain. 

Crossing the blood-brain barrier

As befits a precious organ, the brain is quite well-protected by its bony, fluid- insulated case and by the ‘blood-brain barrier’ that protects it from many blood-borne chemical challenges to its homeostasis, including cellular toxins inimical to neurons. However, of course, many small molecules, including agents that may be therapeutic for infections or other illnesses affecting other organs, may yet be deleterious to brain function. These include, for instance, not only environmental chemicals such as pesticides, under suspicion as possible neurotoxins, but also drugs used to treat cancer, asthma, high cholesterol levels, cardiovascular problems, diabetes, and those affecting the immune system.


Virtually all effective drugs are almost bound to have some ‘adverse side-effects’ which can be the product of a drug’s non-specific modes of action, or may simply reflect effects at other receptors distal from the therapeutic target. Many of these ‘side effects’ are not serious and simply have to be tolerated by the patient. Other effects, such as sedation, for example represent a clear cost, but have to be set against the major benefits of medication. Yet other actions, which may be insidious, can in the long-term be so disadvantageous that the treatment has to be discontinued. All of these considerations of course have to be taken especially seriously during the initial screening or trials of new compounds.  Safety with drugs and other chemicals is paramount, especially when the major functions of the brain, that is to say in producing and regulating behaviour and cognition, are threatened.  This is why toxicology in general and neurotoxicology in particular are nowadays considered to be applied sciences of major importance.


Reliably measure cognitive function

But how does one assess reliably a domain as complex as cognitive functioning? Objective measures are obviously needed, but it is also important to be clear about the nature of such a complex construct. One way to measure intellectual functioning is by means of IQ tests. Although these are undoubtedly useful and important, especially as guides to future academic or career potential, they only provide a coarse and static profile of what we mean by ‘cognition’. Some intellligence tests, particularly those based on verbal IQ, are also rather insensitive to impairments, such as early Alzheimer’s disease. Cognitive Neuroscience now divides up cognition into different neural systems controlling, for example, aspects of perception, attention, short-term and ‘working’ memory, long term memory (e.g. for facts and personal episodes) and language – those processes necessary for representing the world in the brain – and ‘executive functions’ such as planning, decision-making and impulse control, which enable us to make use of those representations and guide the production of thoughts and behaviour. 


Components of Cognition and Cantab


Just as IQ tries to provide a profile of functions (e.g. verbal, performance and memory IQ), in order to determine strengths and weaknesses in an individual’s performance, for the purpose of training or education, for example, it is necessary for a cognitive test battery to provide a similar picture.  For cognition to occur at all, there must be evidence of normal sensory or motor functioning; if the information does not reach the brain or cannot be expressed by it, then clearly cognitive functioning cannot be accurately assessed. Furthermore, it is important to control for comprehension of the tasks and for the motivation to perform them well. When we first started to design the CANTAB battery all of these issues were taken into account.  We had then the innovative idea to use touch-sensitive screens to simplify what was often required of patients or healthy volunteers in terms of arduous paper and pencil tests (reminiscent of school examinations) or even complex computerized arrangements involving attending simultaneously to a screen and a keyboard (not always a favourable multi-tasking situation for many patients). Touching the relevant items in the test is a much more efficient form of deploying attention to them. Of course, this type of thinking is now embodied in the technological triumphs of the iPad and related devices. Naturally, it is important before proceeding to more complex tests to demonstrate that subjects can touch a point accurately on the screen and to respond quickly and efficiently to such stimuli. 


Other tests using the matching-to-sample principle for computer-generated visual icons can be used to infer visual perception, and even for recognising such stimuli after a short delay. This type of test had already been employed in influential studies of monkeys and other animals to determine some of the neural system substrates of memory capacities. In fact, many, though not all, of the CANTAB tests have been based on paradigms derived from research with experimental animals. This means that they are generally non-verbal in nature, one advantage being that they are potentially culture-free and do not have to be translated across many languages. Other non-verbal memory tests such as the paired associates learning task requires subjects to remember and to learn the locations of several different visual objects on the computer screen. This ‘binding’ of information form two distinct information-processing streams, visual objects and space, which is one of the functions of the hippocampus (which is vulnerable to early-onset Alzheimer’s disease, leading ultimately to dementia).


CANTAB has also taken classical clinical neuropsychological tests and simplified them for the purpose of testing patients, decomposing their complex requirements into their constituents and ensuring that subjects can undertake the simpler requirements of the tests before proceeding to the more complex stages. This is exemplified by the way in which a classical test of cognitive flexibility, the Wisconsin Card Sorting Test, is turned into a series of linked simpler tests which occur in a precise order. If a subject fails at any stage, then they do not proceed to the next stage (unknown to the participant), as they would have little hope of achieving it. In this way, frustrating elements of failure are also minimized in the testing situation.


The CANTAB battery also provides visually attractive and fun tests of planning (“Stockings of Cambridge”) and decision-making (“The Cambridge Gambling Task”), as well as versions of sophisticated and informative tests from the psychological research literature such as the stop-signal and reaction time tasks, which assess the ability to stop an action and thus exert volitional control over impulsive behaviour, and finally spatial working memory, which assesses the strategy you employ during working memory to encode spatial information.

Tracking deficits and improvements

The validity of these tests has depended on demonstrating specific and sometimes subtle deficits in these component cognitive functions in groups of patients or in healthy volunteers administered psychoactive drugs such as methylphenidate (or Ritalin). Sometimes effects are detected in patients at risk for clinical syndromes (e.g. in HIV patients and in clinically pre-manifest, genetically-confirmed patients with Huntington’s disease). In both of these cases there is an insidious accumulation of harmful agents in the brain. Dose-dependent deficits are observed with drugs such as scopolamine, the anti-cholinergic agent, and improvements with drugs such as the atypical stimulant modafinil. Deficits or improvements can be measured accurately in relation to the standardized scores for the tests as a function of age and IQ.


Combined with brain imaging methodologies, many of the CANTAB tests have also been shown to be useful for defining the specific network of brain structures responsible for their performance, for example, comprising the prefrontal cortex, parietal lobe and striatum, in the case of visuospatial planning. Correspondingly, a failure on a task (such as the Stockings of Cambridge test of planning) may suggest some form of impairment in that specific brain system. 



Components of Cognition and Cantab


All of these attributes are most desirable in a test battery seeking to define objective profiles of cognitive performance following exposure to a potential neurotoxin, agent or drug with adverse sequelae. The CANTAB battery provides a full profile of cognitive deficits in the memory and executive domains and its capacity to assess the components of cognition represented in Figure 1 is shown in Figure 2. We are hoping that the battery will ultimately be developed further to include further tests of emotional and social cognitive functions (“emotional intelligence”), but already in its present configuration we are confident that the CANTAB battery will provide a major weapon in the armoury of methods used for screening chemicals for harmful effects on cognition and the brain.

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