Financial returns on R&D: looking back at history, looking forward to adaptive licensing.

Investment in R&D for drugs launched in the late 1970s to early 1990s generated good returns for investors. R&D was inexpensive. Clinical trial success rates were high. Consumption was increasing. Drug prices were outstripping inflation, which raised profit margins. Tax rates were falling. However, returns on R&D have been falling since the early 1990s given rising clinical trial costs, rising trial failure rates, and lower consumption growth in developed markets. Many investors believe that average financial returns on today's R&D will be below the cost of capital, particularly if US drug price inflation moderates. Thus R&D investment by major drug companies is flat or perhaps falling in real terms. Various regulatory initiatives have tried to streamline clinical development and approval. The latest is Adaptive Licensing (AL). The near-term effect of AL on industry-level financial returns will be modest. AL will, however, be salient for decisions to invest in specific trials and may make it easier for smaller companies to fund development. AL could become more important in the long run if it helps shift industry, regulators, and payers from what has been an increasingly linear model of innovation; predicated on the ideas that basic science predicts, trials test predictions, and trial results form a complete description of a drug's attributes. History shows that many drugs become important because doctors and patients discover utility that was not initially apparent to regulators, payers, or investors. One hope for AL, therefore, is that it will bring more acceptably safe chemical diversity into real world use at lower R&D cost.

A four year retrospective study of 1,062 patients presenting with maxillofacial emergencies at a specialist paediatric hospital.

AIMS: To examine the nature of maxillofacial injuries that presented to the Birmingham Children's Hospital according to aetiology, incidence and characteristics of patients. METHODS: The maxillofacial unit at Diana Princess of Wales Birmingham Children's Hospital serves a catchment area of 5.2 million. We examined all children who presented with maxillofacial trauma from 2002 to 2006. Details including characteristics of patients and aetiology and nature of injury, were entered prospectively into a database. RESULTS: The total number of patients who presented was 1062. The ratio of boys to girls was 2:1. The main reason for attendance was a fall (70%). 149 (17%) patients presented after interpersonal violence. Soft tissue injuries accounted for 70% of injuries and 14% presented with a maxillofacial fracture. CONCLUSIONS: Our data indicate that the range and mechanism of presenting injuries have not changed within the time frame. Despite public perception of increasing interpersonal violence, this was not reflected in our series of patients.

Is reduced dermatoglyphic a-b ridge count a reliable marker of developmental impairment in schizophrenia?

BACKGROUND: Finger and hand prints are formed during the late first and second trimester of foetal development, after which they remain unchanged. Their expression may be influenced by both genetic and environmental factors. Some studies have suggested that a reduced total finger ridge count (TFRC) and, in particular, a reduce total a-b ridge count (TABRC), may be associated with schizophrenia. AIM: To study these two variables in a large, ethnically homogenous sample and to compare our findings with those of other recent studies. METHOD: Finger and hand prints of 150 people with DSM-III-R schizophrenia were compared with those of 92 healthy controls. RESULTS: Patients had a reduced mean TABRC (P = 0.03) compared with controls. There was a significant (P=0.02) linear trend for lower TABRC and increasing incidence of schizophrenia (ORlineartrend = 1.3; 95%CI1.1-1.7), implying a continuous increase in the risk for schizophrenia with reduction in TABRC. No significant difference between groups was observed for TFRC. CONCLUSION: These results provide further evidence that dermatoglyphic abnormalities exist in at least some patients with schizophrenia and that the a-b ridge count may be a marker of disruption, probably environmental, that occurs when the developing brain may also be particularly vulnerable to such insult. These findings support the concept that some cases of schizophrenia may be due to adverse intrauterine events.

Prey scan at random to evade observant predators.

Anti-predator scans by animals occur with very irregular timing, so that the initiation of scans resembles a random, Poisson-like, process. At first sight, this seems both dangerous (predators could exploit the long intervals) and wastefull (scans after very short intervals are relatively uninformative). We explored vigilance timing using a new model that allows both predators and prey to vary their behaviour. Given predators that attack at random with respect to prey behaviour, constant inter-scan intervals minimize predation risk. However, if prey scan regularly to minimize their risk from randomly attacking predators, they become more vulnerable to predators that initiate attacks when the inter-scan intervals begin. If, in order to defeat this tactic, prey choose extremely variable inter-scan intervals, they become more vulnerable to predators who wait for long intervals before launching attacks. Only if predators can monitor the variability of inter-scan intervals and either attack immediately (if variability is too low) or wait for long intervals to attack (if variability is too high) does the empirically observed pattern of Poisson-like scanning become the optimal prey strategy.

On variability in the density of corticocortical and thalamocortical connections.

Variability is an important but neglected aspect of connectional neuroanatomy. The quantitative density of the 'same' corticocortical or thalamocortical connection may vary by over two orders of magnitude between different injections of the same tracer. At present, however, the frequency distribution of connection densities is unknown. Therefore, it is unclear what kind of sampling strategies or statistical methods are appropriate for quantitative studies of connectivity. Nor is it clear if the measured variability represents differences between subjects, or if it is simply a consequence of intra-individual differences resulting from experimental technique and the exact placement of tracers relative to local spatial and laminar variation in connectivity. We used quantitative measurements of the density of a large number of corticocortical and thalamocortical connections from our own laboratories and from the literature. Variability in the density of given corticocortical and thalamocortical connections is high, with the standard deviation of density proportional to the mean. The frequency distribution is close to exponential. Therefore, analysis methods relying on the normal distribution are not appropriate. We provide an appendix that gives simple statistical guidance for samples drawn from exponentially distributed data. For a given corticocortical or thalamocortical connection density, between-individual standard deviation is 0.85 to 1.25 times the within-individual standard deviation. Therefore, much of the variability reported in conventional neuroanatomical studies (with one tracer deposited per animal) is due to within-individual factors. We also find that strong, but not weak, corticocortical connections are substantially more variable than thalamocortical connections. We propose that the near exponential distribution of connection densities is a simple consequence of 'patchy' connectivity. We anticipate that connection data will be well described by the negative binomial, a class of distribution that applies to events occurring in clumped or patchy substrates. Local patchiness may be a feature of all corticocortical connections and could explain why strong corticocortical connections are more variable than strong thalamocortical connections. This idea is supported by the columnar patterns of many corticocortical but few thalamocortical connections in the literature.

Anatomical connectivity defines the organization of clusters of cortical areas in the macaque monkey and the cat.

The number of different cortical structures in mammalian brains and the number of extrinsic fibres linking these regions are both large. As with any complex system, systematic analysis is required to draw reliable conclusions about the organization of the complex neural networks comprising these numerous elements. One aspect of organization that has long been suspected is that cortical networks are organized into 'streams' or 'systems'. Here we report computational analyses capable of showing whether clusters of strongly interconnected areas are aspects of the global organization of cortical systems in macaque and cat. We used two different approaches to analyse compilations of corticocortical connection data from the macaque and the cat. The first approach, optimal set analysis, employed an explicit definition of a neural 'system' or 'stream', which was based on differential connectivity. We defined a two-component cost function that described the cost of the global cluster arrangement of areas in terms of the areas' connectivity within and between candidate clusters. Optimal cluster arrangements of cortical areas were then selected computationally from the very many possible arrangements, using an evolutionary optimization algorithm. The second approach, non-parametric cluster analysis (NPCA), grouped cortical areas on the basis of their proximity in multidimensional scaling representations. We used non-metric multidimensional scaling to represent the cortical connectivity structures metrically in two and five dimensions. NPCA then analysed these representations to determine the nature of the clusters for a wide range of different cluster shape parameters. The results from both approaches largely agreed. They showed that macaque and cat cortices are organized into densely intra-connected clusters of areas, and identified the constituent members of the clusters. These clusters reflected functionally specialized sets of cortical areas, suggesting that structure and function are closely linked at this gross, systems level.

On imputing function to structure from the behavioural effects of brain lesions.

What is the link, if any, between the patterns of connections in the brain and the behavioural effects of localized brain lesions? We explored this question in four related ways. First, we investigated the distribution of activity decrements that followed simulated damage to elements of the thalamocortical network, using integrative mechanisms that have recently been used to successfully relate connection data to information on the spread of activation, and to account simultaneously for a variety of lesion effects. Second, we examined the consequences of the patterns of decrement seen in the simulation for each type of inference that has been employed to impute function to structure on the basis of the effects of brain lesions. Every variety of conventional inference, including double dissociation, readily misattributed function to structure. Third, we tried to derive a more reliable framework of inference for imputing function to structure, by clarifying concepts of function, and exploring a more formal framework, in which knowledge of connectivity is necessary but insufficient, based on concepts capable of mathematical specification. Fourth, we applied this framework to inferences about function relating to a simple network that reproduces intact, lesioned and paradoxically restored orientating behaviour. Lesion effects could be used to recover detailed and reliable information on which structures contributed to particular functions in this simple network. Finally, we explored how the effects of brain lesions and this formal approach could be used in conjunction with information from multiple neuroscience methodologies to develop a practical and reliable approach to inferring the functional roles of brain structures.

Neuronal population activity and functional imaging.

Human functional brain imaging detects blood flow changes that are thought to reflect the activity of neuronal populations and, thus, the responses of neurons that carry behaviourally relevant information. Since this relationship is poorly understood, we explored the link between the activity of single neurons and their neuronal population. The functional imaging results were in good agreement with levels of population activation predicted from the known effects of sensory stimulation, learning and attention on single cortical neurons. However, the nature of the relationship between population activation and single neuron firing was very surprising. Population activation was strongly influenced by those neurons firing at low rates and so was very sensitive to the baseline or 'spontaneous' firing rate. When neural representations were sparse and neurons were tuned to several stimulus dimensions, population activation was hardly influenced by the few neurons whose firing was most strongly modulated by the task or stimulus. Measures of population activation could miss changes in information processing given simultaneous changes in neurons' baseline firing, response modulation or tuning width. Factors that can modulate baseline firing, such as attention, may have a particularly large influence on population activation. The results have implications for the interpretation of functional imaging signals and for cross-calibration between different methods for measuring neuronal activity.

The smell map: is there a commonality of odour perception?

The normal perception of odour quality is poorly understood, so formulating meaningful tests of olfaction is difficult. While tests of odour discrimination and odour detection threshold have helped quantify olfactory dysfunction, there are not yet predictive relationships between sensitivity to particular odours and particular forms of olfactory dysfunction. Using 11 commonly encountered odours, 20 normosmics performed similarity ratings of odour pairs. Multidimensional scaling, a standard behavioural sciences data analysis method, was used to explore the perceptual relationships between the odours based on their pair-wise similarity ratings. Smell maps were created for each individual as was a common or archetypal map which indicated a commonality in individuals' odour perception, far greater than chance alone (P < 10(-6)). A preliminary analysis of four hyposmics suggests that they do not conform to the normosmic archetype. Future studies assessing the relationship between odours in the archetype should improve the selection of odours to be included in tests of odour discrimination.

The connectional organization of the cortico-thalamic system of the cat.

Data on connections between the areas of the cerebral cortex and nuclei of the thalamus are too complicated to analyse with naked intuition. Indeed, the complexity of connection data is one of the major challenges facing neuroanatomy. Recently, systematic methods have been developed and applied to the analysis of the connectivity in the cerebral cortex. These approaches have shed light on the gross organization of the cortical network, have made it possible to test systematically theories of cortical organization, and have guided new electrophysiological studies. This paper extends the approach to investigate the organization of the entire cortico-thalamic network. An extensive collation of connection tracing studies revealed approximately 1500 extrinsic connections between the cortical areas and thalamic nuclei of the cat cerebral hemisphere. Around 850 connections linked 53 cortical areas with each other, and around 650 connections linked the cortical areas with 42 thalamic nuclei. Non-metric multidimensional scaling, optimal set analysis and non-parametric cluster analysis were used to study global connectivity and the 'place' of individual structures within the overall scheme. Thalamic nuclei and cortical areas were in intimate connectional association. Connectivity defined four major thalamo-cortical systems. These included three broadly hierarchical sensory or sensory/motor systems (visual and auditory systems and a single system containing both somatosensory and motor structures). The highest stations of these sensory/motor systems were associated with a fourth processing system composed of prefrontal, cingulate, insular and parahippocampal cortex and associated thalamic nuclei (the 'fronto-limbic system'). The association between fronto-limbic and somato-motor systems was particularly close.