Arturo Tozzi

Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease

The financial support of Telethon–Italy (grant E791) is gratefully acknowledged. This work was also funded by the Italian Telethon Foundation, the Italian Ministry of Health, and the European Community (contract MH4-CT97-2107).

Effect of the dietary fiber glucomannan on chronic constipation in neurologically impaired children

OBJECTIVE Inadequate dietary fiber intake is a widely accepted explanation for chronic constipation in children with severe brain damage. The aim of our study was to evaluate the efficacy of glucomannan, a soluble fiber, as a treatment for chronic constipation in these children. STUDY DESIGN Twenty children with severe brain damage and chronic constipation were randomly assigned to double-blind treatment with either glucomannan (n = 10) or placebo (n = 10) for 12 weeks. Stool habits, total and segmental gastrointestinal transit times, and anorectal motility were evaluated in all children before and after the treatment period. RESULTS Glucomannan significantly increased (P <.01) stool frequency, whereas the effect of placebo was not significant. Laxative or suppository use was significantly reduced (P <.01) by glucomannan but was not affected by placebo. Clinical scores of stool consistency were significantly improved and episodes of painful defecation per week were significantly reduced by glucomannan (P <.01) but not by placebo. However, neither glucomannan nor placebo had a measurable effect on total and segmental transit times. CONCLUSIONS In neurologically impaired children, glucomannan improves stool frequency but has no effect on colonic motility.

Letters to the EditorDouble Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease

The financial support of Telethon–Italy (grant E791) is gratefully acknowledged. This work was also funded by the Italian Telethon Foundation, the Italian Ministry of Health, and the European Community (contract MH4-CT97-2107).

Towards a Neuronal Gauge Theory

In a published paper [10], we have proposed that the brain (and other self-organized biological and artificial systems) can be characterized via the mathematical apparatus of a gauge theory. The picture that emerges from this approach suggests that any biological system (from a neuron to an organism) can be cast as resolving uncertainty about its external milieu, either by changing its internal states or its relationship to the environment. Using formal arguments, we have shown that a gauge theory for neuronal dynamics – based on approximate Bayesian inference – has the potential to shed new light on phenomena that have thus far eluded a formal description, such as attention and the link between action and perception. Here, we describe the technical apparatus that enables such a variational inference on manifolds.Given the amount of knowledge and data accruing in the neurosciences, is it time to formulate a general principle for neuronal dynamics that holds at evolutionary, developmental, and perceptual timescales? In this paper, we propose that the brain (and other self-organised biological systems) can be characterised via the mathematical apparatus of a gauge theory. The picture that emerges from this approach suggests that any biological system (from a neuron to an organism) can be cast as resolving uncertainty about its external milieu, either by changing its internal states or its relationship to the environment. Using formal arguments, we show that a gauge theory for neuronal dynamics—based on approximate Bayesian inference—has the potential to shed new light on phenomena that have thus far eluded a formal description, such as attention and the link between action and perception.

Towards a fourth spatial dimension of brain activity

Current advances in neurosciences deal with the functional architecture of the central nervous system, paving the way for general theories that improve our understanding of brain activity. From topology, a strong concept comes into play in understanding brain functions, namely, the 4D space of a “hypersphere’s torus”, undetectable by observers living in a 3D world. The torus may be compared with a video game with biplanes in aerial combat: when a biplane flies off one edge of gaming display, it does not crash but rather it comes back from the opposite edge of the screen. Our thoughts exhibit similar behaviour, i.e. the unique ability to connect past, present and future events in a single, coherent picture as if we were allowed to watch the three screens of past-present-future “glued” together in a mental kaleidoscope. Here we hypothesize that brain functions are embedded in a imperceptible fourth spatial dimension and propose a method to empirically assess its presence. Neuroimaging fMRI series can be evaluated, looking for the topological hallmark of the presence of a fourth dimension. Indeed, there is a typical feature which reveal the existence of a functional hypersphere: the simultaneous activation of areas opposite each other on the 3D cortical surface. Our suggestion—substantiated by recent findings—that brain activity takes place on a closed, donut-like trajectory helps to solve long-standing mysteries concerning our psychological activities, such as mind-wandering, memory retrieval, consciousness and dreaming state.

A topological approach unveils system invariances and broken symmetries in the brain

Symmetries are widespread invariances underscoring countless systems, including the brain. A symmetry break occurs when the symmetry is present at one level of observation but is hidden at another level. In such a general framework, a concept from algebraic topology, namely, the Borsuk‐Ulam theorem (BUT), comes into play and sheds new light on the general mechanisms of nervous symmetries. The BUT tells us that we can find, on an n‐dimensional sphere, a pair of opposite points that have the same encoding on an n – 1 sphere. This mapping makes it possible to describe both antipodal points with a single real‐valued vector on a lower dimensional sphere. Here we argue that this topological approach is useful for the evaluation of hidden nervous symmetries. This means that symmetries can be found when evaluating the brain in a proper dimension, although they disappear (are hidden or broken) when we evaluate the same brain only one dimension lower. In conclusion, we provide a topological methodology for the evaluation of the most general features of brain activity, i.e., the symmetries, cast in a physical/biological fashion that has the potential to be operationalized.

Persistence of abnormal gastrointestinal motility after operation for Hirschsprung's disease

OBJECTIVE:Recent studies in patients with Hirschsprungs disease (HD) suggest that morphological abnormalities of the intramural intestinal plexuses are not restricted to the colon. In this report, symptoms and objective tests of gastrointestinal (GI) motor dysfunction were determined long after operative treatment to see whether evidence of a more widespread and relevant motility disturbance could be detected.METHODS:Twenty-one children were available for study an average of 6.6 yr after surgery for HD. All of these patients underwent evaluation of bowel frequency per week, total GI transit time (TGTT), and a scintigraphic gastric emptying test using solid food; anorectal manometry and segmental colonic transit times were performed in a subset of patients. Results were compared with findings in appropriately matched controls.RESULTS:Frequency of defecation per week in patients with HD after surgery was not different from that in control children, but TGTT was significantly longer (p < 0.01). Percentage retention of gastric isotope at 60 min exceeded the normal range in 12 of 21 (57.1%) patients, and colonic transit was abnormal in all six children studied. Symptoms persisted in two-thirds of patients postoperatively, and transit abnormalities were more common in the symptomatic subset (p = 0.026).CONCLUSIONS:Our data show that, in a subset of patients with HD, GI motor dysfunction persists long after surgical correction. The heterogeny of basic defects responsible for HD could provide the substrate for these motor abnormalities that, in turn, seem at least partially responsible for continuation of the symptomatic state.

Information processing in the CNS: a supramolecular chemistry?

How does central nervous system process information? Current theories are based on two tenets: (a) information is transmitted by action potentials, the language by which neurons communicate with each other—and (b) homogeneous neuronal assemblies of cortical circuits operate on these neuronal messages where the operations are characterized by the intrinsic connectivity among neuronal populations. In this view, the size and time course of any spike is stereotypic and the information is restricted to the temporal sequence of the spikes; namely, the “neural code”. However, an increasing amount of novel data point towards an alternative hypothesis: (a) the role of neural code in information processing is overemphasized. Instead of simply passing messages, action potentials play a role in dynamic coordination at multiple spatial and temporal scales, establishing network interactions across several levels of a hierarchical modular architecture, modulating and regulating the propagation of neuronal messages. (b) Information is processed at all levels of neuronal infrastructure from macromolecules to population dynamics. For example, intra-neuronal (changes in protein conformation, concentration and synthesis) and extra-neuronal factors (extracellular proteolysis, substrate patterning, myelin plasticity, microbes, metabolic status) can have a profound effect on neuronal computations. This means molecular message passing may have cognitive connotations. This essay introduces the concept of “supramolecular chemistry”, involving the storage of information at the molecular level and its retrieval, transfer and processing at the supramolecular level, through transitory non-covalent molecular processes that are self-organized, self-assembled and dynamic. Finally, we note that the cortex comprises extremely heterogeneous cells, with distinct regional variations, macromolecular assembly, receptor repertoire and intrinsic microcircuitry. This suggests that every neuron (or group of neurons) embodies different molecular information that hands an operational effect on neuronal computation.

Clinical response to amino acid-based formula in neurologically impaired children with refractory esophagitis.

Objective Chronic gastrointestinal symptoms and histologic changes of the esophagus unresponsive to standard treatments for gastroesophageal reflux disease (GERD) may be improved by the use of elemental formulas. The aim of our study was to evaluate the efficacy of a dietary trial in neurologically impaired children unresponsive to medical and surgical therapy for GERD. Methods Nine children (three boys and six girls; median age, 44 months; range, 13–180 months) affected by cerebral palsy associated with severe mental retardation and with long-standing history of GERD were fed the elemental formula, Neocate, for a minimum of 4 weeks. Before and after the dietary trial, each child underwent endoscopy with esophageal biopsy and a cellobiose/mannitol sugar permeability test. The diagnosis of GERD was based on the microscopic changes of the esophagus. Results Before the dietary trial, according to conventional histologic criteria, esophagitis was considered moderate in seven children and mild in two. Five of nine patients also had abnormal sugar permeability test results. During and after the dietary trial, seven of nine patients experienced resolution of their long-term symptom complaints. Furthermore, after the dietary trial, both endoscopic (P < 0.01) and histologic (P < 0.05) findings significantly improved. At 6-month follow-up, progressive reintroduction of individual dietary proteins, except for cows milk protein, did not cause reappearance of the symptoms. Conclusions In neurologically impaired children unresponsive to conventional antireflux treatments, a course of a highly restricted diet with an amino acid–based formula may bring an immediate and sustained, endoscopically and histologically proven improvement in long-standing gastrointestinal symptoms and esophagitis.

From abstract topology to real thermodynamic brain activity

Recent approaches to brain phase spaces reinforce the foremost role of symmetries and energy requirements in the assessment of nervous activity. Changes in thermodynamic parameters and dimensions occur in the brain during symmetry breakings and transitions from one functional state to another. Based on topological results and string-like trajectories into nervous energy landscapes, we provide a novel method for the evaluation of energetic features and constraints in different brain functional activities. We show how abstract approaches, namely the Borsuk–Ulam theorem and its variants, may display real, energetic physical counterparts. When topology meets the physics of the brain, we arrive at a general model of neuronal activity, in terms of multidimensional manifolds and computational geometry, that has the potential to be operationalized.