Imran Noorani

An internationally standardised antisaccade protocol

Detailed measurements of saccadic latency--the time taken to make an eye movement to a suddenly-presented visual target--have proved a valuable source of detailed and quantitative information in a wide range of neurological conditions, as well as shedding light on the mechanisms of decision, currently of intense interest to cognitive neuroscientists. However, there is no doubt that more complex oculomotor tasks, and in particular the antisaccade task in which a participant must make a saccade in the opposite direction to the target, are potentially more sensitive indicators of neurological dysfunction, particularly in neurodegenerative conditions. But two obstacles currently hinder their widespread adoption for this purpose. First, that much of the potential information from antisaccade experiments, notably about latency distribution and amplitude, is typically thrown away. Second, that there is no standardised protocol for carrying out antisaccade experiments, so that results from one laboratory cannot easily be compared with those from another. This paper, the outcome of a recent international meeting of oculomotor scientists and clinicians with an unusually wide experience of such measurements, sets out a proposed protocol for clinical antisaccade trials: its adoption will greatly enhance the clinical and scientific benefits of making these kinds of measurements.

The LATER model of reaction time and decision.

How do we choose one option rather than another when faced with uncertainty about the information we receive, and the consequences of what we decide? The LATER (Linear Approach to Threshold with Ergodic Rate) model has proved to be remarkably accurate in predicting how we respond in such situations. Given its conceptual simplicity, its grounding in fundamental Bayesian principles and its very few free parameters, it is being increasingly adopted for a wider range of choice tasks, helping us to understand the underlying neural mechanisms, and in applying this to clinical disorders. Here, we provide a thorough discussion of the history behind this model, and how it can be applied to more complex decisions, including anti-saccades, Go-NoGo, countermanding and other situations where newly-arriving information means that ongoing decisions must be modified. The neuroscience of decision-making is progressing rapidly, and we anticipate that wider understanding and application of this model will help simplify the interpretation of increasingly advanced decision behaviour both in the laboratory and clinic.

Full reaction time distributions reveal the complexity of neural decision-making.

Measurement of the stochastic distribution of reaction time or latency has become a popular technique that can potentially provide precise, quantitative information about the underlying neural decision mechanisms. However, this approach typically requires data from large numbers of individual trials, in order to enable reliable distinctions to be made between different models of decision. When data are not plentiful, an approximation to full distributional information can be provided by using a small number of quantiles instead of full distributions – often, just five are used. Although this can often be adequate when the proposed underlying model is a relatively simple one, we show here that, with more complex tasks, and correspondingly extended models, this kind of approximation can often be extremely misleading, and may hide important features of the underlying mechanisms that only full distributional analysis can reveal.

Predicting the timing of wrong decisions with LATER

Response time, or latency, is increasingly being used to provide information about neural decision processes. LATER (Linear Approach to Threshold with Ergodic Rate) is a quasi-Bayesian model of decision-making, with the additional feature that it introduces a degree of gratuitous randomisation into the decision process. It has had some success in predicting latencies under various conditions, but has not specifically been applied to an equally important aspect of decision-making, namely errors: a complete model of decision-making should not only account for latency distributions of correct decisions but also of wrong ones. We therefore used a decision task that generates large numbers of errors: subjects are told to look at suddenly appearing targets of one colour, but not another. We found that subjects’ faster responses are as likely to be correct as wrong, but eventually the latency distributions diverge, with errors becoming infrequent. It seems that colour information, arriving after a delay, results both in cancellation of the developing response to the mere existence of the target and in delayed initiation of the correct response. A simple model, using LATER units in a similar way to one that has previously successfully modelled countermanding, accurately predicts latency distributions and proportions of all responses, whether correct or incorrect, demonstrating that the LATER model can indeed account for errors as well as correct responses.

Re‐starting a neural race: anti‐saccade correction

In the anti‐saccade task, a subject must make a saccadic eye movement in the opposite direction from a suddenly‐presented visual target. This sets up a conflict between the natural tendency to make a pro‐saccade towards the target and the required anti‐saccade. Consequently there is a tendency to make errors, usually corrected by a second movement in the correct anti‐saccade direction. In a previous paper, we showed that a very simple model, with racing LATER (Linear Approach to Threshold at Ergodic Rate) units for the pro‐ and anti‐directions, and a stop unit that inhibits the impending error response, could account precisely for the detailed distributions of reaction times both for correct and error responses. However, the occurrence and timing of these final corrections have not been studied. We propose a novel mechanism: the decision race re‐starts after an error. Here we describe measurements of all the responses in an anti‐saccade task, including corrections, in a group of human volunteers, and show that the timing of the corrections themselves can be predicted by the same model with one additional assumption, that initiation of an incorrect pro‐saccade also resets and initiates a corrective anti‐saccade. No extra parameters are needed to predict this complex aspect of behaviour, adding weight to our proposal that we correct our mistakes by re‐starting a neural decision race. The concept of re‐starting a decision race is potentially exciting because it implies that neural processing of one decision can influence the next, and may be a fruitful way of understanding the complex behaviour underlying sequential decisions.

Towards a unifying mechanism for cancelling movements

For precise motor control, we must be able to not only initiate movements with appropriate timing, but also stop them. The importance of stopping tended to be overlooked in research in favour of studying movement itself, so we are still only beginning to understand the neural basis of action cancellation. However, the development of models of behaviour in a wider range of tasks, and their relation to neural recordings has provided great insight into the underlying neurophysiology. Here we focus on developments of the linear approach to threshold with ergodic rate (LATER) model, relating these to complementary neurophysiological studies. It is tempting to consider that there may be a unifying mechanism for cancelling impending decisions in many contexts and how future efforts may clarify this possibility. This article is part of the themed issue ‘Movement suppression: brain mechanisms for stopping and stillness’.

Ultrafast initiation of a neural race by impending errors

The brain makes decisions by means of races between neural units representing alternative choices. In the present study, we record the eyemovements made in the Wheeless task, when a visual stimulus is followed after a short delay by another stimulus demanding a different response. The behaviour can be very precisely described as a race between three independent decision processes: one Go process for each of the responses, and a Stop process that tries to cancel the first, now erroneous, response. To explain the high success rate for cancellation that we observe, the onset time for the Stop process must be some 10–20 ms shorter than for Go. As well as extending our understanding of the dynamics of complex decision‐making, this task provides a rapid, non‐invasive method for quantifying disorders of higher neural function.

Basal ganglia: racing to say no

How we choose one action over another has intrigued neuroscientists for decades. Early models of decision-making involved a race between processes representing alternative choices. To explain behaviour in complex decisions, for example, where one must cancel an impending action, a Stop unit must also join the race. Recent neuronal recordings have demonstrated just such a race between Go and Stop processes in the basal ganglia. This is a landmark advance because it neurophysiologically justifies the need for a Stop process in such tasks, and very likely in other behaviours requiring rapid cancellation of impending actions.

Not moving: the fundamental but neglected motor function

The function of the motor system in preventing rather than initiating movement is often overlooked. Not only are its highest levels predominantly, and tonically, inhibitory, but in general behaviour it is often intermittent, characterized by relatively short periods of activity separated by longer periods of stillness: for most of the time we are not moving, but stationary. Furthermore, these periods of immobility are not a matter of inhibition and relaxation, but require us to expend almost as much energy as when we move, and they make just as many demands on the central nervous system in controlling their performance. The mechanisms that stop movement and maintain immobility have been a greatly neglected area of the study of the brain. This paper introduces the topics to be examined in this special issue of Philosophical Transactions, discussing the various types of stopping and stillness, the problems that they impose on the motor system, the kinds of neural mechanism that underlie them and how they can go wrong. This article is part of the themed issue ‘Movement suppression: brain mechanisms for stopping and stillness’.

Novel association between microglia and stem cells in human gliomas: A contributor to tumour proliferation?

Brain tumour stem cells and microglia both promote the growth of astrocytomas, the commonest form of primary brain tumour, with recent emerging evidence that these cell types may interact in glioma models. It is unclear whether microglia and stem cells are associated in human gliomas. To investigate this question, we used the technique of tissue microarrays to perform a correlative study of a large number of tumour samples. We quantified immunostaining of human astrocytic tumour tissue microarrays (86 patients; World Health Organisation grade II–IV) for microglia Ionized calcium binding adaptor molecule 1 (Iba1) and CD68, and stem cell nestin, SOX2 and CD133. Ki67 was used to assess proliferation and GFAP for astrocytic differentiation. Immunoreactivity for both microglial markers and stem cell markers nestin and SOX2 significantly increased with increasing tumour grade. GFAP was higher in low grade astrocytomas. There was a positive correlation between: (i) both microglial markers and nestin and CD133, (ii) nestin and tumour cell proliferation Ki67 and (iii) both microglial markers and Ki67. SOX2 was not associated with microglia or tumour proliferation. To test the clinical relevance, we investigated the putative association of these markers with clinical outcomes. High expression for nestin and Iba1 correlated with significantly shorter survival times, and high expression for nestin, Iba1, CD68 and Ki67 was associated with faster tumour progression on univariate analysis. On multivariate analysis, nestin, CD133 and Ki67 remained significant predictors of poorer survival, after adjustment for other markers. These results confirm previous in vitro findings, demonstrating their functional relevance as a therapeutic target in humans. This is the first report of a novel correlation between microglia and stem cells that may drive human astrocytic tumour development.