Fractal Electronics for Stimulating and Sensing Neural Networks: Enhanced Electrical, Optical, and Cell Interaction Properties.

Imagine a world in which damaged parts of the body - an arm, an eye, and ultimately a region of the brain - can be replaced by artificial implants capable of restoring or even enhancing human performance. The associated improvements in the quality of human life would revolutionize the medical world and produce sweeping changes across society. In this chapter, we discuss several approaches to the fabrication of fractal electronics designed to interface with neural networks. We consider two fundamental functions - stimulating electrical signals in the neural networks and sensing the location of the signals as they pass through the network. Using experiments and simulations, we discuss the favorable electrical performances that arise from adopting fractal rather than traditional Euclidean architectures. We also demonstrate how the fractal architecture induces favorable physical interactions with the cells they interact with, including the ability to direct the growth of neurons and glia to specific regions of the neural-electronic interface.

Impact of small-angle scattering on ballistic transport in quantum dots.

Disorder increasingly affects performance as electronic devices are reduced in size. The ionized dopants used to populate a device with electrons are particularly problematic, leading to unpredictable changes in the behavior of devices such as quantum dots each time they are cooled for use. We show that a quantum dot can be used as a highly sensitive probe of changes in disorder potential and that, by removing the ionized dopants and populating the dot electrostatically, its electronic properties become reproducible with high fidelity after thermal cycling to room temperature. Our work demonstrates that the disorder potential has a significant, perhaps even dominant, influence on the electron dynamics, with important implications for "ballistic" transport in quantum dots.

How neurons exploit fractal geometry to optimize their network connectivity.

We investigate the degree to which neurons are fractal, the origin of this fractality, and its impact on functionality. By analyzing three-dimensional images of rat neurons, we show the way their dendrites fork and weave through space is unexpectedly important for generating fractal-like behavior well-described by an 'effective' fractal dimension D. This discovery motivated us to create distorted neuron models by modifying the dendritic patterns, so generating neurons across wide ranges of D extending beyond their natural values. By charting the D-dependent variations in inter-neuron connectivity along with the associated costs, we propose that their D values reflect a network cooperation that optimizes these constraints. We discuss the implications for healthy and pathological neurons, and for connecting neurons to medical implants. Our automated approach also facilitates insights relating form and function, applicable to individual neurons and their networks, providing a crucial tool for addressing massive data collection projects (e.g. connectomes).

Evaluation of three approaches to meniscal release.

Three approaches to medial meniscal release (MMR) were compared using 48 canine cadaver stifles. The approaches included a caudomedial arthrotomy approach, a blind stab incision based on anatomic landmarks, and an arthroscopic guided approach. The cranial cruciate ligament was intact in all specimens. The time required to perform the meniscal release and joint capsule closure was recorded, as well as completeness and location of the meniscal transection. Damage to the caudal cruciate ligament, femoral cartilage, and medial collateral ligament were recorded. The mini-arthrotomy was 81% successful in accomplishment of MMR with a 4% rate of iatrogenic damage. The blind technique was 56% successful in the accomplishment of MMR with a 4% rate of iatrogenic damage. The arthroscopic guided approach was 62.5% successful in accomplishment of MMR, with a 10% rate of iatrogenic damage. Accomplishment and iatrogenic damage rates were not significantly different among procedures (p > 0.05). Significantly less time was required to perform the blind technique, and significantly greater time was required to perform the arthroscopic guided technique (p > 0.05). Significant differences were not noted among the procedures regarding the ability to accomplish the meniscal release or damage surrounding structures. None of the evaluated approaches for meniscal release resulted in a complete and accurate meniscal release for over 81% of the time.

Fractal Electrodes as a Generic Interface for Stimulating Neurons.

The prospect of replacing damaged body parts with artificial implants is being transformed from science fiction to science fact through the increasing application of electronics to interface with human neurons in the limbs, the brain, and the retina. We propose bio-inspired electronics which adopt the fractal geometry of the neurons they interface with. Our focus is on retinal implants, although performance improvements will be generic to many neuronal types. The key component is a multifunctional electrode; light passes through this electrode into a photodiode which charges the electrode. Its electric field then stimulates the neurons. A fractal electrode might increase both light transmission and neuron proximity compared to conventional Euclidean electrodes. These advantages are negated if the fractal's field is less effective at stimulating neurons. We present simulations demonstrating how an interplay of fractal properties generates enhanced stimulation; the electrode voltage necessary to stimulate all neighboring neurons is over 50% less for fractal than Euclidean electrodes. This smaller voltage can be achieved by a single diode compared to three diodes required for the Euclidean electrode's higher voltage. This will allow patients, for the first time, to see with the visual acuity necessary for navigating rooms and streets.

Seeing shapes in seemingly random spatial patterns: Fractal analysis of Rorschach inkblots.

Rorschach inkblots have had a striking impact on the worlds of art and science because of the remarkable variety of associations with recognizable and namable objects they induce. Originally adopted as a projective psychological tool to probe mental health, psychologists and artists have more recently interpreted the variety of induced images simply as a signature of the observers' creativity. Here we analyze the relationship between the spatial scaling parameters of the inkblot patterns and the number of induced associations, and suggest that the perceived images are induced by the fractal characteristics of the blot edges. We discuss how this relationship explains the frequent observation of images in natural scenery.

Significance of serum complement levels in patients with gastrointestinal disease.

Levels of the serum complement components, C3 and C4, in patients with Crohn's disease, ulcerative colitis, and miscellaneous gastrointestinal disorders were compared with those of normal blood donors. Significant increases of both components were found in all three patient groups, the highest being in patients with Crohn's disease. Generally, levels of C3 and C4 were lower in patients with inactive rather than active Crohn's disease and ulcerative colitis. These results provide some evidence in support of an immunological basis for inflammatory bowel disease. However, in view of the frequent elevation of C3 and C4 in other gastrointestinal diseases, it is equally possible that the complement components are behaving as acute phase proteins.

HTLV-1 and tropical spastic paraparesis. 1. Clinical features, pathology and epidemiology.

The clinical profile of tropical spastic paraparesis (TSP), described in scattered tropical and subtropical territories over the past 30 years, has been more clearly defined since the discovery of its direct association with human T lymphotropic virus type 1 (HTLV-1). A chronic disease of adults, commoner in women, it usually presents as a progressive spastic paraparesis with sphincter disturbance, sometimes with backache and lower limb sensory disorder. Most cases are chair-bound within 10 years. Histology reveals a chronic lymphocytic meningomyelopathy, predominantly in the spinal cord, together with long tract demyelination and hyalinoid thickening of the media and adventitia of small blood vessels. Geographical areas of high prevalence of TSP are known in the Caribbean, South America, South Africa, southern Japan, the Seychelles and probably in India, and it is sparsely endemic elsewhere. The virus appears to exist within lymphocytes for long periods. Vertical transmission occurs postnatally, and sexual and transfusion infection are also recognized, but much remains to be clarified regarding its pathogenesis and epidemiology.

The epidemiology of myelopathy associated with human T-lymphotropic virus 1.

A progressive spastic myelopathy is one of the principal manifestations of the human T cell lymphotropic virus type 1. Recent research is reviewed on the geography and epidemiology of this specific form of tropical spastic paraparesis. First recognized in the Caribbean, Colombia and Japan, it is now also confirmed as a major neurological problem in areas of eastern Brazil, western equatorial Africa, Natal and Seychelles, with other scattered foci world-wide. Accurate surveys call for sophisticated techniques including polymerase chain reaction amplification. The only defined modes of spread are by breast feeding, sexual contact and blood cell infusion. The onset of neurological disease is associated with high antibody titres and a high rate of spontaneous T lymphocyte proliferation. Molecular analysis has revealed no nucleotide sequence variation in cases with or without myelopathy. In non-transfusion cases the clinical attack rate is low with a very long latent period, but there are unexplained regional differences and familial cases are an important exception. Current research is focused on possible local, ethnic, or genetic co-factors.

Post-infective malabsorption in the temperate zone.

A series of 37 adults normally resident in Britain have been investigated for persistent bowel symptoms following acute enteritis. 26 had intestinal malabsorption, of whom 12 had been travelling in the Mediterranean area, whereas 10 developed their illness at home. Mild jejunal mucosal abnormalities were found in cases with and without malabsorption, and the intraepithelial lymphocyte count correlated more closely with the degree of malabsorption than did the histological grading. Over 80% of severe cases were folate deficient. Enterobacteria were cultured from the jejunal fluid in 30% of cases. Our observations confirm that post-infective malabsorption occurs sporadically in adults in the temperate zone and is occasionally severe. The condition involves small bowel contamination with enterobacteria, and it differs from acute tropical sprue only in its greater tendency to spontaneous recovery.

Intestinal absorption in Saudi Arabia: an evaluation of the one hour blood xylose test.

The screening value of the one-hour blood xylose test, corrected for body surface area, was prospectively studied in Saudi Arabian adults and children under investigation for suspected intestinal malabsorption. Sensitivity of discrimination between patients with and without upper small bowel disease was 91%, compared to 85% for the five-hour urine xylose test. Primary small bowel disorder was rare. In a three-year review, no cases of adult coeliac disease or tropical sprue were found. The most common causes of malabsorption were intestinal tuberculosis, abdominal lymphoma and immunoproliferative small intestinal disease. Despite its acceptability as an index of proximal small bowel function, the blood xylose test alone is an inadequate screening test for any of these conditions.

Use of a 35.5 kDa cell membrane composition of Pasteurella multocida and an anti-idiotype antibody to induce protective immunity in leghorn chickens.

Using polyacrylamide gel electrophoresis and Western blot analysis, a 35.5 kDa cell membrane composition of Pasteurella multocida ATCC 11039 was identified as a dominant epitope of the bacterium. Mice inoculated with inactivated whole bacteria produce antisera primary reactive with the 35.5 kDa component (Pm35.5) in Western blot analysis. The outer membrane component was composed primarily of protein but did have lipopolysaccharide present at 133 micrograms mg-1 protein. In challenge trials (Trial 2), groups of white leghorn chickens vaccinated with Pm35.5 or an anti-idiotypic antibody (using Pm35.5 as the original antigen) had significant difference in mortality of 3.2% and 48.3%, respectively, when compared with unvaccinated controls (99%). Mortality in a group of chickens receiving a commercially available bacterin (9.2%) was higher but not significantly different from the mortality of the Pm35.5 vaccinated group (3.2%).

The reharvested central third of the patellar tendon. A histologic and biomechanical analysis.

We assessed the histologic, mechanical, and structural properties of the reharvested central-third patellar tendon in greyhounds. Twelve dogs had the central third of the patellar tendon (5 mm) removed with corresponding bone blocks from the patella and tibia; the remaining tendon defect was loosely closed. Six dogs were sacrificed at 6 months and six at 12 months, and the central third of the patellar tendon was harvested from both the operative and the contralateral control knees. Analysis of the structural changes in the tendons revealed a significant increase in thickness for reharvested tendons at both 6 and 12 months when compared with controls. The entire residual tendons were narrower at 6 months and were shorter at 12 months compared with controls. Mechanical testing showed that the average failure load, ultimate tensile strength, strain at failure, and average modulus for the reharvested central third of the patellar tendon were significantly less than that of controls at both 6 and 12 months. Analysis of collagen fiber size by electron microscopy revealed a significant increase in collagen fiber diameter at 6 months (135 +/- 41 nm versus 49 +/- 4 nm) but no difference between the operative limbs and controls at 12 months. The reharvested bone-patellar tendon-bone complex does not have the same properties as the primary patellar tendon graft up to 1 year after harvest in a canine model, and its use for revision cruciate ligament reconstruction must be carefully reexamined.

Winner of the AlbertTrillat Young Investigator Award. The effects of aggressive notchplasty on the normal knee in dogs.

We assessed the possible association between an aggressive intercondylar notchplasty and histopathologic, radiographic, and gait changes to the knee. Three groups of six adult greyhounds were observed for 6 months. Group I dogs had a sham operation. Group II dogs had a 4-mm notchplasty of the lateral femoral condyle where it articulates with the lateral tibial spine. Group III dogs had a 7- to 8-mm notchplasty of the lateral femoral condyle to simulate the long-term effects of an overly aggressive notchplasty. Force plate gait analyses were not significantly different for any dogs at 3 and 6 months. Histopathologic studies (hematoxylin and eosin and safranin O stains) revealed notchplasty area remodeling with a thin layer of lamellar bone covered by fibrous connective tissue. Both Group II and III dogs had significant loss of lateral femoral condyle and trochlear groove articular surface proteoglycans. The radiographic notch width index remained unchanged throughout the study for Group I; the indexes increased immediately after surgery in Groups II and III because of the notchplasty, but after 6 months these values returned to near-preoperative measurements. An aggressive intercondylar notchplasty caused articular cartilage histopathologic changes at 6 months consistent with those found in knees with early degenerative arthritis. Significant refilling of a non-impinged notchplasty occurred by 6 months after surgery. Our results raise concern about the effects of aggressive intercondylar notch widening in humans.

The effect of Harderian adenectomy on the antibody response in chickens.

Intact chicks and those that had their glands of Harder (GH) removed (GHx) at 1 day of age were studied for their response to optically or intraperitoneally (IP) applied antigens. Following exposure of the chicks to sheep red blood cells (SRBCs), killed Brucella abortus, or bovine serum albumin (BSA), serum and tear samples were collected and assayed for antibodies. Of the two sources of antibodies, the serum generally had higher levels than did the tears. The only exception to this occurred in the intact chicks inoculated by the eye, in which serum and tear levels were equivalent. With SRBCs, no difference could be detected between the two routes of inoculation. However, IP inoculation produced higher levels of antibody in the serum of intact and GHx chicks inoculated with B. abortus or BSA and in the tears of the GHx chicks exposed to B. abortus. Removal of the GH resulted in a consistent decrease in antibody levels in the tears, regardless of the route of exposure. Although this effect was noted with all three antigens, it was more pronounced in the trials using B. abortus and BSA. This finding is discussed in terms of describing the importance of the GH as a source of antibodies to optically applied antigens, and its importance as a route of circulating antibody egress. Furthermore, the feasibility of using the antibody response in tears to a test antigen is discussed as a means of measuring the immune status of a functioning GH.

A comparison of the gland of Harder response and head-associated lymphoid tissue (HALT) morphology in chickens and turkeys.

The immunofunctional response of the gland of Harder (GH) was compared in chickens and turkeys using an in vivo assay previously developed for use in chickens. The GH were surgically removed (GHx) from leghorn chicks at 1 day of age and from poults at 2 days of age. Intact birds of each species served as controls. During the fourth week of age, both GH-intact and GHx chicks were exposed to killed Brucella abortus antigen by the ocular or intraperitoneal route. One week later, serum and tears were collected and assayed for antibodies to B. abortus. In addition, all birds were killed at the end of the trial period, and the heads were fixed and processed for histologic examination. Various components of the head-associated lymphoid tissue (HALT) including the GH, nasal glands, lacrimal glands, lacrimal ducts, eyelid conjunctiva, and nasal cavity mucosa/submucosa, were evaluated microscopically using a scoring system to estimate quantity and degree of development of immune tissue in those sites. Results of all analyses indicate that functional response and morphology of the HALT are comparable in turkeys and chickens.

Effect of infectious bursal disease virus vaccines on persistence and pathogenicity of modified live reovirus vaccines in chickens.

Two commercially available live reovirus vaccines, alone or in combination with two infectious bursal disease virus (IBDV) vaccines, were evaluated for safety and efficacy in specific-pathogen-free leghorn chicks. Four trials were conducted to evaluate the vaccine combinations. At periodic intervals during the trials, tissues were collected and assayed for residual reovirus and examined for histological changes. Six weeks following reovirus vaccination, all treatment groups were challenged with a virulent field isolate of reovirus and sampled 1 week later for the final time. The two reovirus vaccines were safe and effective if given at 1 week of age, regardless of whether the vaccinates had been exposed to IBDV at 1 day. However, both reovirus vaccines persisted in the tendons of 1-day-old vaccinates. The effects of IBDV vaccines were generally minor and reflected by increases in the number of pre-challenge or post-challenge virus recoveries from some of the treatment groups receiving both type vaccines.

Persistence of commercial modified live reovirus vaccines in chicks.

Four modified live reovirus vaccines were compared with a field isolate (81-176) of reovirus for safety in 1-day-old and 1-wk-old specific-pathogen-free chicks. At 1, 3, 5, and 7 wks after vaccination, blood, cloacal swabs, and hock tendon samples were collected and assayed for residual virus. Tendon samples were also examined microscopically and scored for histological changes. Vaccine efficacy was monitored by challenging chicks 7 wks postvaccination via the footpad with the 81-176 isolate. Serum samples were collected throughout the trials and assayed for reovirus antibodies using an enzyme-linked immunosorbent assay. In chicks vaccinated at 1 day of age, three of the four vaccine viruses were consistently recovered from the hock tendon tissues. Post-challenge virus recoveries were similarly positive for the same vaccine viruses. Histological lesion scores of the tendons paralleled the degree of virus recovery. In the chicks vaccinated at 1 wk old, none of the vaccine viruses were recovered, nor were tendon lesion scores substantially elevated. Following challenge, however, virus was recovered from all vaccinated groups.

Role of route of exposure, age, sex, and type of chicken on the pathogenicity of avian reovirus strain 81-176.

Chickens were evaluated by age, sex, and type for susceptibility to reovirus strain 81-176 inoculated subcutaneously. Chicks were most susceptible to the lethal effects of reovirus infection at hatching, after which resistance increased rapidly. By 1 week of age, mortality was negligible, but chicks were still susceptible to the less lethal effects of the virus. Mortality rates of males and females were equal. Leghorn and broiler-type chicks did not differ appreciably in their response to viral inoculation. An effort was made to find a more "natural" means of exposure to reovirus than parenteral inoculation. Neither oral nor aerosol exposure was as effective as subcutaneous inoculation. Attempts to transmit reovirus to susceptible hatching chicks, starting when they were in ovo (19 days of incubation), also failed. Decreased weight gain proved to be a valid criterion for judging reovirus infection. Reovirus infection lowered the mean values of body weights, and the standard deviations were substantially greater, indicating an unevenness in size of the affected chickens.

Observations on the pathogenicity of Alcaligenes faecalis in chickens.

A series of trials was conducted in which specific-pathogen-free (SPF) leghorn chicks were exposed to various isolates of Alcaligenes faecalis. Chicks were inoculated with A. faecalis alone or in combination with Newcastle disease/infectious bronchitis (Nc/Br) vaccine, laryngotracheitis vaccine, infectious bursal disease virus, or Mycoplasma gallisepticum. The response was evaluated by morbidity, mortality, airsacculitis, reisolation of A. faecalis, and histopathological lesions of tracheas. Although A. faecalis was recovered up to 42 days postinoculation in some cases, no clinical signs were directly attributed to simple A. faecalis infection. None of the other agents significantly increased the severity of A. faecalis signs or lesions, except that A. faecalis-infected chicks that were given Nc/Br vaccine had prolonged microscopic tracheal lesions. In another trial, the effects of A. faecalis in young SPF leghorns, non-SPF broilers, and turkeys were compared. Broiler-type chicks were more susceptible than leghorns and less susceptible than poults. Consequently, the use of leghorns as a model for studying this infection is questioned.