Cortical Models for Movement Control

Defense Advanced Research Projects Agency and Office of Naval Research (N0014-95-l-0409)

Evaluation of behavior in transgenic mouse models to understand human congenital pain conditions

BACKGROUND: Containing a brain for signal processing and decision making, and a peripheral component for sensation and response, the nervous system provides higher organisms a powerful method of interacting with their environment. The specific neurons involved in pain sensation are known as nociceptors and are the source of normal nociceptive pain signaling to prompt appropriate responses. Though acute hypersensitization can be advantageous by encouraging an organism to allow an injured area to heal, chronic pain conditions can be pathological and can markedly reduce quality of life. While a variety of genes have been associated with congenital pain conditions, two rare cases examined in this study have not had their mutated genes identified. Potassium voltage-gated channel subfamily H member 8, or KCNH8, is involved in regulating action potential production and propagation, and has not been linked with pain processing of any kind to date. Here, a male patient evaluated at Boston Children’s Hospital contains a novel single-base KCNH8 mutation and possesses an extremely low sensitivity to cold temperatures and mechanical pain, but a higher sensitivity to warmer temperatures. A separate protein, intersectin-2, or ITSN2, normally functions in clathrin-mediated endocytosis and exocytosis. A second patient at Boston Children’s Hospital expresses a previously-unseen point mutation in ITSN2 and experiences erythromelalgia, characterized by episodes of intense pain and red, swollen limbs during ambient warm temperatures. Through the use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome editing, this study will produce these specific genetic mutations in mouse lines to explore their effects on mammalian behavior. OBJECTIVES: This project employs two transgenic mouse models to study the behavioral phenotypes associated with rare potentially damaging mutations in KCNH8 and ITSN2 exhibited in the human patients. Through these experiments, a greater understanding of neural pain signaling and sensitivity changes can occur. METHODS: The differences in temperature preference of KCNH8 and ITSN2 mutant mice compared to wild type mice lacking these mutations was studied using thermal plates under cold and warm conditions. Direct application of acetone and von Frey filaments to mouse paws was used to study cold and mechanical sensitivity. Further testing of stamina, anxiety, coordination, and strength were also evaluated. RESULTS: A marked decrease in sensitivity to von Frey stimulation (p<0.01) and acetone administration (p<0.05) was observed in KCNH8 mutant mice. Thermal preference testing demonstrated a decreased preference for warmer temperatures as compared to wild type mice. In addition, anxiety levels were also observed to be slightly higher in these mutant KCNH8 mice (p<0.05). The mutant ITSN2 mice spent less time at cooler temperatures, though surprisingly they significantly preferred warmer conditions as compared to their wild type littermates. A full and partial reversal of these temperature preferences was demonstrated in cold and heat thermal conditions respectively after intraperitoneal gabapentin injection, which normalized the mice toward wild type behavior. CONCLUSIONS: Data from the KCNH8 mutant mouse model indicates an aversion to warmer temperatures and a decreased ability to detect cold or mechanical pressure, much like the human patient. The mutant ITSN2 mice were less likely to spend time at cooler temperatures, indicating heightened sensory sensitivity, but their preference for warmer temperatures suggests a possible desensitization of the affected nociceptors. These results often mirror the patient’s phenotype, but the preference for ambient warmer environments appears opposite to the patient. As the ITSN2 mice feel discomfort at cooler temperatures, a proposed desensitization at warmer temperatures would result in a more comfortable environment and could explain the observed preference. The trends toward normal neural firing rates achieved through gabapentin injection suggest that the aberrant responses in mutant ITSN2 mice is due to altered sensitization, but additional examination under these conditions with a larger group of mice is necessary to further unravel these signaling pathways. However, these extremely encouraging data introduce two new molecular targets for acute pain control

From Parallel Sequence Representations to Calligraphic Control: A Conspiracy of Neural Circuits

Calligraphic writing presents a rich set of challenges to the human movement control system. These challenges include: initial learning, and recall from memory, of prescribed stroke sequences; critical timing of stroke onsets and durations; fine control of grip and contact forces; and letter-form invariance under voluntary size scaling, which entails fine control of stroke direction and amplitude during recruitment and derecruitment of musculoskeletal degrees of freedom. Experimental and computational studies in behavioral neuroscience have made rapid progress toward explaining the learning, planning and contTOl exercised in tasks that share features with calligraphic writing and drawing. This article summarizes computational neuroscience models and related neurobiological data that reveal critical operations spanning from parallel sequence representations to fine force control. Part one addresses stroke sequencing. It treats competitive queuing (CQ) models of sequence representation, performance, learning, and recall. Part two addresses letter size scaling and motor equivalence. It treats cursive handwriting models together with models in which sensory-motor tmnsformations are performed by circuits that learn inverse differential kinematic mappings. Part three addresses fine-grained control of timing and transient forces, by treating circuit models that learn to solve inverse dynamics problems.National Institutes of Health (R01 DC02852

An evolutionary advantage for extravagant honesty

A game-theoretic model of handicap signalling over a pair of signalling channels is introduced in order to determine when one channel has an evolutionary advantage over the other. The stability conditions for honest handicap signalling are presented for a single channel and are shown to conform with the results of prior handicap signalling models. Evolutionary simulations are then used to show that, for a two-channel system in which honest signalling is possible on both channels, the channel featuring larger advertisements at equilibrium is favoured by evolution. This result helps to address a significant tension in the handicap principle literature. While the original theory was motivated by the prevalence of extravagant natural signalling, contemporary models have demonstrated that it is the cost associated with deception that stabilises honesty, and that the honest signals exhibited at equilibrium need not be extravagant at all. The current model suggests that while extravagant and wasteful signals are not required to ensure a signalling system's evolutionary stability, extravagant signalling systems may enjoy an advantage in terms of evolutionary attainability

The fallacy of general purpose bio-inspired computing

Bio-inspired computing comes in many flavours, inspired by biological systems from which salient features and/or organisational principles have been idealised and abstracted. These bio-inspired schemes have sometimes been demonstrated to be general purpose; able to approximate arbitrary dynamics, encode arbitrary structures, or even carry out universal computation. The generality of these abilities is typically (although often implicitly) reasoned to be an attractive and worthwhile trait. Here, it is argued that such reasoning is fallacious. Natural systems are nichiversal rather than universal, and we should expect the computational systems that they inspire to be similarly limited in their performance, even if they are ultimately capable of generality in their competence. Practical and methodological implications of this position for the use of bio-inspired computing within artificial life are outlined

Adaptive Neural Models of Queuing and Timing in Fluent Action

Temporal structure in skilled, fluent action exists at several nested levels. At the largest scale considered here, short sequences of actions that are planned collectively in prefrontal cortex appear to be queued for performance by a cyclic competitive process that operates in concert with a parallel analog representation that implicitly specifies the relative priority of elements of the sequence. At an intermediate scale, single acts, like reaching to grasp, depend on coordinated scaling of the rates at which many muscles shorten or lengthen in parallel. To ensure success of acts such as catching an approaching ball, such parallel rate scaling, which appears to be one function of the basal ganglia, must be coupled to perceptual variables, such as time-to-contact. At a fine scale, within each act, desired rate scaling can be realized only if precisely timed muscle activations first accelerate and then decelerate the limbs, to ensure that muscle length changes do not under- or over-shoot the amounts needed for the precise acts. Each context of action may require a much different timed muscle activation pattern than similar contexts. Because context differences that require different treatment cannot be known in advance, a formidable adaptive engine-the cerebellum-is needed to amplify differences within, and continuosly search, a vast parallel signal flow, in order to discover contextual "leading indicators" of when to generate distinctive parallel patterns of analog signals. From some parts of the cerebellum, such signals controls muscles. But a recent model shows how the lateral cerebellum, such signals control muscles. But a recent model shows how the lateral cerebellum may serve the competitive queuing system (in frontal cortex) as a repository of quickly accessed long-term sequence memories. Thus different parts of the cerebellum may use the same adaptive engine system design to serve the lowest and the highest of the three levels of temporal structure treated. If so, no one-to-one mapping exists between levels of temporal structure and major parts of the brain. Finally, recent data cast doubt on network-delay models of cerebellar adaptive timing.National Institute of Mental Health (R01 DC02852

Prospects for large-scale financial systems simulation

As the 21st century unfolds, we find ourselves having to control, support, manage or otherwise cope with large-scale complex adaptive systems to an extent that is unprecedented in human history. Whether we are concerned with issues of food security, infrastructural resilience, climate change, health care, web science, security, or financial stability, we face problems that combine scale, connectivity, adaptive dynamics, and criticality. Complex systems simulation is emerging as the key scientific tool for dealing with such complex adaptive systems. Although a relatively new paradigm, it is one that has already established a track record in fields as varied as ecology (Grimm and Railsback, 2005), transport (Nagel et al., 1999), neuroscience (Markram, 2006), and ICT (Bullock and Cliff, 2004). In this report, we consider the application of simulation methodologies to financial systems, assessing the prospects for continued progress in this line of research

United States Tort Liability for War Crimes Abroad: An Assessment and Recommendation

Bullock proposes that victims of war crimes be permitted to recover against the US government through administrative procedures similar to those of the Foreign Claims Act