Elementary units of cortical activity? The rise and fall of the cortical column

The roots of the concept of cortical columns stretch far back into the history of neuroscience. The impulse to compartmentalise the cortex into functional units can be seen at work in the phrenology of the beginning of the nineteenth century. At the beginning of the next century Korbinian Brodmann and several others published treatises on cortical architectonics. Later, in the middle of that century, Lorente de No writes of chains of ‘reverberatory’ neurons orthogonal to the pial surface of the cortex and called them ‘elementary units of cortical activity’. This is the first hint that a columnar organisation might exist. With the advent of microelectrode recording first Vernon Mountcastle (1957) and then David Hubel and Torsten Wiesel provided evidence consistent with the idea that columns might constitute units of physiological activity. This idea was backed up in the 1970s by clever histochemical techniques and culminated in Hubel and Wiesel’s well-known ‘ice-cube’ model of the cortex and Szentogathai’s brilliant iconography. The cortical column can thus be seen as the terminus ad quem of several great lines of neuroscientific research: currents originating in phrenology and passing through cytoarchitectonics; currents originating in neurocytology and passing through Lorente de No. Famously, Huxley noted the tragedy of a beautiful hypothesis destroyed by an ugly fact. Famously, too, human visual perception is orientated toward seeing edges and demarcations when, perhaps, they are not there. Recently the concept of cortical columns has come in for the same radical criticism that undermined the architectonics of the early part of the twentieth century. Does history repeat itself? This paper reviews this history and asks the question.

Functional characterization of GABAergic pallidopallidal and striatopallidal synapses in the rat globus pallidus in vitro

As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. Driven by intrinsic mechanisms and excitatory glutamatergic inputs from the subthalamic nucleus, GP neurons receive GABAergic inhibitory input from the striatum (Str-GP) and from local collaterals of neighbouring pallidal neurons (GP-GP). Here we provide electrophysiological evidence for functional differences between these two inhibitory inputs. The basic synaptic characteristics of GP-GP and Str-GP GABAergic synapses were studied using whole-cell recordings with paired-pulse and train stimulation protocols and variance-mean (VM) analysis. We found (i) IPSC kinetics are consistent with local collaterals innervating the soma and proximal dendrites of GP neurons whereas striatal inputs innervate more distal regions. (ii) Compared to GP-GP synapses Str-GP synapses have a greater paired-pulse ratio, indicative of a lower probability of release. This was confirmed using VM analysis. (iii) In response to 20 and 50 Hz train stimulation, GP-GP synapses are weakly facilitatory in 1 mm external calcium and depressant in 2.4 mm calcium. This is in contrast to Str-GP synapses which display facilitation under both conditions. This is the first quantitative study comparing the properties of GP-GP and Str-GP synapses. The results are consistent with the differential location of these inhibitory synapses and subtle differences in their release probability which underpin stable GP-GP responses and robust short-term facilitation of Str-GP responses. These fundamental differences may provide the physiological basis for functional specialization.

Clustering of cerebral cortical lesions in patients with corticobasal degeneration

Clustering of ballooned neurons (BN) and tau positive neurons with inclusion bodies (tau+ neurons) was studied in the upper and lower laminae of the frontal, parietal and temporal cortex in 12 patients with corticobasal degeneration (CBD). In a significant proportion of brain areas examined, BN and tau+ neurons exhibited clustering with a regular distribution of clusters parallel to the pia mater. A regular pattern of clustering of BN and tau+ neurons was observed equally frequently in all cortical areas examined and in the upper and lower laminae. No significant correlations were observed between the cluster sizes of BN or tau+ neurons in the upper compared with the lower cortex or between the cluster sizes of BN and tau+ neurons. The results suggest that BN and tau+ neurons in CBD exhibit the same type of spatial pattern as lesions in Alzheimer's disease, Lewy body dementia and Pick's disease. The regular periodicity of the cerebral cortical lesions is consistent with the degeneration of the cortico-cortical projections in CBD.

Evaluation of the importance of astrocytes when screening for acute toxicity in neuronal cell systems

Reliable, high throughput, in vitro preliminary screening batteries have the potential to greatly accelerate the rate at which regulatory neurotoxicity data is generated. This study evaluated the importance of astrocytes when predicting acute toxic potential using a neuronal screening battery of pure neuronal (NT2.N) and astrocytic (NT2.A) and integrated neuronal/astrocytic (NT2.N/A) cell systems derived from the human NT2.D1 cell line, using biochemical endpoints (mitochondrial membrane potential (MMP) depolarisation and ATP and GSH depletion). Following exposure for 72 h, the known acute human neurotoxicants trimethyltin-chloride, chloroquine and 6-hydroxydopamine were frequently capable of disrupting biochemical processes in all of the cell systems at non-cytotoxic concentrations. Astrocytes provide key metabolic and protective support to neurons during toxic challenge in vivo and generally the astrocyte containing cell systems showed increased tolerance to toxicant insult compared with the NT2.N mono-culture in vitro. Whilst there was no consistent relationship between MMP, ATP and GSH log IC(50) values for the NT2.N/A and NT2.A cell systems, these data did provide preliminary evidence of modulation of the acute neuronal toxic response by astrocytes. In conclusion, the suitability of NT2 neurons and astrocytes as cell systems for acute toxicity screening deserves further investigation.

The role of stochasticity in an information-optimal neural population code

In this paper we consider the optimisation of Shannon mutual information (MI) in the context of two model neural systems The first is a stochastic pooling network (population) of McCulloch-Pitts (MP) type neurons (logical threshold units) subject to stochastic forcing; the second is (in a rate coding paradigm) a population of neurons that each displays Poisson statistics (the so called 'Poisson neuron'). The mutual information is optimised as a function of a parameter that characterises the 'noise level'-in the MP array this parameter is the standard deviation of the noise, in the population of Poisson neurons it is the window length used to determine the spike count. In both systems we find that the emergent neural architecture and; hence, code that maximises the MI is strongly influenced by the noise level. Low noise levels leads to a heterogeneous distribution of neural parameters (diversity), whereas, medium to high noise levels result in the clustering of neural parameters into distinct groups that can be interpreted as subpopulations In both cases the number of subpopulations increases with a decrease in noise level. Our results suggest that subpopulations are a generic feature of an information optimal neural population.

CADS*: Computer-Aided Development of self-* systems

We present the prototype tool CADS* for the computer-aided development of an important class of self-* systems, namely systems whose components can be modelled as Markov chains. Given a Markov chain representation of the IT components to be included into a self-* system, CADS* automates or aids (a) the development of the artifacts necessary to build the self-* system; and (b) their integration into a fully-operational self-* solution. This is achieved through a combination of formal software development techniques including model transformation, model-driven code generation and dynamic software reconfiguration.

An age-related increase in resistance to DNA damage-induced apoptotic cell death is associated with development of DNA repair mechanisms

Neurons in the developing brain die via apoptosis after DNA damage, while neurons in the adult brain are generally resistant to these insults. The basis for this resistance is a matter of conjecture. We report here that cerebellar granule neurons (CGNs) in culture lose their competence to die in response to DNA damage as a function of time in culture. CGNs at either 1 day in vitro (DIV) or 7 DIV were treated with the DNA damaging agents camptothecin, UV or gamma-irradiation and neuronal survival measured. The younger neurons were effectively killed by these agents, while the older neurons displayed a significant resistance to killing. Neuronal survival did not change with time in culture when cells were treated with C2-ceramide or staurosporine, agents which do not target DNA. The resistance to UV irradiation developed over time in culture and was not due to changes in mitotic rate. Increases in DNA strand breakage, up-regulation of the levels of both p53 and its phosphorylated form and nuclear translocation of p53 were equivalent in both older and younger neurons, indicating a comparable p53 stress response. In addition, we show that treatment of older neurons with pharmacological inhibitors of distinct components of the DNA repair machinery promotes the accumulation of DNA damage and sensitizes these cells to the toxic effects of UV exposure. These data demonstrate that older neurons appear to be more proficient in DNA repair in comparison to their younger counterparts, and that this leads to increased survival after DNA damage.

A quantitative study of the pathological changes in the cortical white matter in variant Creutzfeldt-Jakob disease (vCJD)

The objective of this study was to determine the degree of white matter pathology in the cerebral cortex in cases of variant Creutzfeldt-Jakob disease (vCJD) and to study the relationships between the white matter and grey matter pathologies. Hence, the pathological changes in cortical white matter were studied in individual gyri of the frontal, parietal, occipital, and temporal cortex in eleven cases of vCJD. Vacuolation (‘spongiform change’), deposition of the disease form of prion protein (PrPsc) in the form of discrete PrP deposits, and gliosis were observed in the white matter of virtually all cortical regions studied. Mean density of the vacuoles in the white matter was greater in the parietal lobe compared with the frontal, occipital, and temporal lobes but there were fewer glial cells in the occipital lobe compared with the other cortical regions. In the white matter of the frontal cortex, vacuole density was negatively correlated with the density of both glial cell nuclei and the PrP deposits. In addition, the densities of glial cells and PrP deposits were positively correlated in the frontal and parietal cortex. In the white matter of the frontal cortex and inferior temporal gyrus, there was a negative correlation between the densities of the vacuoles and the number of surviving neurons in laminae V/VI of the adjacent grey matter. In addition, in the frontal cortex, vacuole density in the white matter was negatively correlated with the density of the diffuse PrP deposits in laminae II/III and V/VI of the adjacent grey matter. The densities of PrP deposits in the white matter of the frontal cortex were positively correlated with the density of the diffuse PrP deposits in laminae II/III and V/V1 and with the number of surviving neurons in laminae V/V1. The data suggest that in the white matter in vCJD, gliosis is associated with the development of PrP deposits while the appearance of the vacuolation is a later development. In addition, neuronal loss and PrP deposition in the lower cortical laminae of the grey matter may be a consequence of axonal degeneration within the white matter.

Differential localization of GABAA receptor subunits in relation to rat striatopallidal and pallidopallidal synapses

As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. The GP is composed of a network of inhibitory GABA-containing projection neurons which receive GABAergic input from axons of the striatum (Str) and local collaterals of GP neurons. Here, using electrophysiological techniques and immunofluorescent labeling we have investigated the differential cellular distribution of a1, a2 and a3 GABAA receptor subunits in relation to striatopallidal (Str-GP) and pallidopallidal (GP-GP) synapses. Electrophysiological investigations showed that zolpidem (100 nm; selective for the a1 subunit) increased the amplitude and the decay time of both Str-GP and GP-GP IPSCs, indicating the presence of the a1 subunits at both synapses. However, the application of drugs selective for the a2, a3 and a5 subunits (zolpidem at 400 nm, L-838,417 and TP003) revealed differential effects on amplitude and decay time of IPSCs, suggesting the nonuniform distribution of non-a1 subunits. Immunofluorescence revealed widespread distribution of the a1 subunit at both soma and dendrites, while double- and triple-immunofluorescent labeling for parvalbumin, enkephalin, gephyrin and the ?2 subunit indicated strong immunoreactivity for GABAAa3 subunits in perisomatic synapses, a region mainly targeted by local axon collaterals. In contrast, immunoreactivity for synaptic GABAAa2 subunits was observed in dendritic compartments where striatal synapses are preferentially located. Due to the kinetic properties which each GABAAa subunit confers, this distribution is likely to contribute differentially to both physiological and pathological patterns of activity.

A quantitative study of the pathological changes in the cortical white matter in variant Creutzfeldt-Jakob disease (vCJD).

Objective: To quantify cortical white matter pathology in variant Creutzfeldt-Jakob disease (vCJD) and to correlate white and grey matter pathologies. Methods: Pathological changes were studied in immunolabeled sections of the frontal, parietal, occipital, and temporal cortex of eleven cases of vCJD. Results: Vacuolation ("spongiform change"), deposition of the disease form of prion protein (PrPsc), and a glial cell reaction were observed in the white matter. The density of the vacuoles was greatest in the white matter of the occipital cortex and glial cell density in the inferior temporal gyrus (ITG). Florid-type PrPsc deposits were present in approximately 50% of white matter regions studied. In the white matter of the frontal cortex (FC), vacuole density was negatively correlated with the densities of both glial cell nuclei and PrPsc deposits. In addition, in the frontal and parietal cortices the densities of glial cells and PrPsc deposits were positively correlated. In the FC and ITG, there was a negative correlation between the densities of the vacuoles in the white matter and the number of surviving neurons in laminae V/VI of the adjacent grey matter. In the FC, vacuole density in the white matter was negatively correlated with the density of the diffuse PrPsc deposits in laminae II/III and V/VI of the adjacent grey matter. In addition, the densities of PrPsc deposits in the white matter of the FC were positively correlated with the density of the diffuse PrPsc deposits in laminae II/III and V/VI and with the number of surviving neurons in laminae V/VI. Conclusion: The data suggest significant degeneration of cortical white matter in vCJD; the vacuolation being related to neuronal loss in the lower cortical laminae of adjacent grey matter, PrPsc deposits the result of leakage from damaged axons, and gliosis a reaction to these changes.

Development of performance models for co-operative information systems in an organisational context

The thesis reports of a study into the effect upon organisations of co-operative information systems (CIS) incorporating flexible communications, group support and group working technologies. A review of the literature leads to the development of a model of effect based upon co-operative business tasks. CIS have the potential to change how co-operative business tasks are carried out and their principal effect (or performance) may therefore be evaluated by determining to what extent they are being employed to perform these tasks. A significant feature of CIS use identified is the extent to which they may be designed to fulfil particular tasks, or by contrast, may be applied creatively by users in an emergent fashion to perform tasks. A research instrument is developed using a survey questionnaire to elicit users judgements of the extent to which a CIS is employed to fulfil a range of co-operative tasks. This research instrument is applied to a longitudinal study of Novell GroupWise introduction at Northamptonshire County Council during which qualitative as well as quantitative data were gathered. A method of analysis of questionnaire results using principles from fuzzy mathematics and artificial intelligence is developed and demonstrated. Conclusions from the longitudinal study include the importance of early experiences in setting patterns for use for CIS, the persistence of patterns of use over time and the dominance of designed usage of the technology over emergent use.

Melting and solidification of Zinc-Aluminium alloys

Following a scene-setting introduction are detailed reviews of the relevant scientific principles, thermal analysis as a research tool and the development of the zinc-aluminium family of alloys. A recently introduced simultaneous thermal analyser, the STA 1500, its use for differential thermal analysis (DTA) being central to the investigation, is described, together with the sources of support information, chemical analysis, scanning electron microscopy, ingot cooling curves and fluidity spiral castings. The compositions of alloys tested were from the binary zinc-aluminium system, the ternary zinc-aluminium-silicon system at 30%, 50% and 70% aluminium levels, binary and ternary alloys with additions of copper and magnesium to simulate commercial alloys and five widely used commercial alloys. Each alloy was shotted to provide the smaller, 100mg, representative sample required for DTA. The STA 1500 was characterised and calibrated with commercially pure zinc, and an experimental procedure established for the determination of DTA heating curves at 10°C per minute and cooling curves at 2°C per minute. Phase change temperatures were taken from DTA traces, most importantly, liquidus from a cooling curve and solidus from both heating and cooling curves. The accepted zinc-aluminium binary phase diagram was endorsed with the added detail that the eutectic is at 5.2% aluminium rather than 5.0%. The ternary eutectic trough was found to run through the points, 70% Al, 7.1% Si, 545°C; 50% Al, 3.9% Si, 520°C; 30% Al, 1.4% Si, 482°C. The dendrite arm spacing in samples after DTA increased with increasing aluminium content from 130m at 30% to 220m at 70%. The smallest dendrite arm spacing of 60m was in the 30% aluminium 2% silicon alloy. A 1kg ingot of the 10% aluminium binary alloy, insulated with Kaowool, solidified at the same 2°C per minute rate as the DTA samples. A similar sized sand casting was solidified at 3°C per minute and a chill casting at 27°C per minute. During metallographic examination the following features were observed: heavily cored phase which decomposed into ' and '' on cooling; needles of the intermetallic phase FeAl4; copper containing ternary eutectic and copper rich T phase.

Cost effectiveness of production control systems

This thesis deals with the problems associated with the planning and control of production, with particular reference to a small aluminium die casting company. The main problem areas were identified as: (a) A need to be able to forecast the customers demands upon the company's facilities. (b) A need to produce a manufacturing programme in which the output of the foundry (or die casting section) was balanced with the available capacity in the machine shop. (c) The need to ensure that the resultant system enabled the company's operating budget to have a reasonable chance of being achieved. At the commencement of the research work the major customers were members of the automobile industry and had their own system of forecasting, from which they issued manufacturing schedules to their component suppliers, The errors in the forecast were analysed and the distributions noted. Using these distributions the customer's forecast was capable of being modified to enable his final demand to be met with a known degree of confidence. Before a manufacturing programme could be developed the actual manufacturing system had to be reviewed and it was found that as with many small companies there was a remarkable lack of formal control and written data. Relevant data with regards to the component and the manufacturing process had therefore to be collected and analysed. The foundry process was fixed but the secondary machining operations were analysed by a technique similar to Component Flow Analysis and as a result the machines were arranged in a series of flow lines. A system of manual production control was proposed and for comparison, a local computer bureau was approached and a system proposed incorporating the production of additional management information. These systems are compared and the relative merits discussed and a proposal made for implementation.

The derivation and application of risk tolerability criteria

This research involves a study of the questions, "what is considered safe", how are safety levels defined or decided, and according to whom. Tolerable or acceptable risk questions raise various issues: about values and assumptions inherent in such levels; about decision-making frameworks at the highest level of policy making as well as on the individual level; and about the suitability and competency of decision-makers to decide and to communicate their decisions. The wide-ranging topics covering philosophical and practical concerns examined in the literature review reveal the multi-disciplined scope of this research. To support this theoretical study empirical research was undertaken at the European Space Research and Technology Centre (ESTEC) of the European Space Agency (ESA). ESTEC is a large, multi-nationality, high technology organisation which presented an ideal case study for exploring how decisions are made with respect to safety from a personal as well as organisational aspect. A qualitative methodology was employed to gather, analyse and report the findings of this research. Significant findings reveal how experts perceive risks and the prevalence of informal decision-making processes partly due to the inadequacy of formal methods for deciding risk tolerability. In the field of occupational health and safety, this research has highlighted the importance and need for criteria to decide whether a risk is great enough to warrant attention in setting standards and priorities for risk control and resources. From a wider perspective and with the recognition that risk is an inherent part of life, the establishment of tolerability risk levels can be viewed as cornerstones indicating our progress, expectations and values, of life and work, in an increasingly litigious, knowledgeable and global society.

The need for and improvement of budgetary planning in a multinational corporation

The aim of this research is to improve the planning methodology of Dunlop via an analysis of their annual planning system. This was approached via an investigation of how the plans were developed; extensive interviews, which analysed divisional attitudes and approaches to planning; an analysis of forecast accuracy; and participation in the planning system itself. These investigations revealed certain deficiencies in the operating of the system. In particular, little evidence of formal planning could be found, and some divisions were reacting ex post to the market, rather than planning ex ante. The resulting plans tended to lack resilience and were generally unrealistic, partly because of imposed targets. Similarly, because the links between the elements of the system were often inefficient, previously agreed strategies were not always implemented. The analysis of forecast accuracy in the plans revealed divisions to be poor at most aspects of forecasting. Simple naive models often outperformed divisional forecasts, and much of the error was attributed to systematic, and therefore eliminable factors. These analyses suggested the need for a new system which is proposed in the form of Budgetary Planning. This system involves conceptual changes within the current planning framework. Such changes aim to revise tactical planning in order to meet the needs placed on it by. in particular, strategic planning. Budgetary Planning is an innovation in terms of the current planning literature. It is a total system of annual planning aimed at implementing and controlling the iteratively agreed strategies within the current environment. This is achieved by the generation of tactical alternatives, variable funding and concentration of forecast credibility, all of which aid both the realism and the resilience of planning.