Bottom-up gamma maintenance in various disorders.

Maintained gamma band activity is a key element of higher brain function, participating in perception, executive function, and memory. The pedunculopontine nucleus (PPN), as part of the reticular activating system (RAS), is a major source of the "bottom-up" flow of gamma activity to higher regions. However, interruption of gamma band activity is associated with a number of neurological and psychiatric disorders. This review will focus on the role of the PPN in activating higher regions to induce arousal and descending pathways to modulate posture and locomotion. As such, PPN deep brain stimulation (DBS) can not only help regulate arousal and stepping, but continuous application may help maintain necessary levels of gamma band activity for a host of other brain processes. We will explore the potential future applications of PPN DBS for a number of disorders that are characterized by disturbances in gamma band maintenance.

The 10 Hz Frequency: A Fulcrum For Transitional Brain States.

A 10 Hz rhythm is present in the occipital cortex when the eyes are closed (alpha waves), in the precentral cortex at rest (mu rhythm), in the superior and middle temporal lobe (tau rhythm), in the inferior olive (projection to cerebellar cortex), and in physiological tremor (underlying all voluntary movement). These are all considered resting rhythms in the waking brain which are "replaced" by higher frequency activity with sensorimotor stimulation. That is, the 10 Hz frequency fulcrum is replaced on the one hand by lower frequencies during sleep, or on the other hand by higher frequencies during volition and cognition. The 10 Hz frequency fulcrum is proposed as the natural frequency of the brain during quiet waking, but is replaced by higher frequencies capable of permitting more complex functions, or by lower frequencies during sleep and inactivity. At the center of the transition shifts to and from the resting rhythm is the reticular activating system, a phylogenetically preserved area of the brain essential for preconscious awareness.

Implications of gamma band activity in the pedunculopontine nucleus.

The fact that the pedunculopontine nucleus (PPN) is part of the reticular activating system places it in a unique position to modulate sensory input and fight-or-flight responses. Arousing stimuli simultaneously activate ascending projections of the PPN to the intralaminar thalamus to trigger cortical high-frequency activity and arousal, as well as descending projections to reticulospinal systems to alter posture and locomotion. As such, the PPN has become a target for deep brain stimulation for the treatment of Parkinson's disease, modulating gait, posture, and higher functions. This article describes the latest discoveries on PPN physiology and the role of the PPN in a number of disorders. It has now been determined that high-frequency activity during waking and REM sleep is controlled by two different intracellular pathways and two calcium channels in PPN cells. Moreover, there are three different PPN cell types that have one or both calcium channels and may be active during waking only, REM sleep only, or both. Based on the new discoveries, novel mechanisms are proposed for insomnia as a waking disorder. In addition, neuronal calcium sensor protein-1 (NCS-1), which is over expressed in schizophrenia and bipolar disorder, may be responsible for the dysregulation in gamma band activity in at least some patients with these diseases. Recent results suggest that NCS-1 modulates PPN gamma band activity and that lithium acts to reduce the effects of over expressed NCS-1, accounting for its effectiveness in bipolar disorder.

Arousal and the control of perception and movement.

Recent discoveries on the nature of the activity generated by the reticular activating system (RAS) suggest that arousal is much more involved in perception and movement than previously thought. The RAS is not simply an amorphous, unspecific region but rather a distinct group of nuclei with specific cell and transmitter types that control waking and modulate such processes as perception and movement. Thus, disturbances in the RAS will affect a number of neurological disorders. The discovery of gamma band activity in the RAS determined that high threshold calcium channels are responsible for generating gamma band activity in the RAS. Results showing that waking is mediated by CaMKII modulation of P/Q-type channels and REM sleep is modulated by cAMP/PK modulation of N-type channels points to different intracellular pathways influencing each state. Few studies address these important breakthroughs. Novel findings also show that the same primate RAS neurons exhibiting activity in relation to arousal are also involved in locomotion. Moreover, deep brain stimulation of this region, specifically the pedunculopontine nucleus (PPN DBS), in Parkinson's disease has salutary effects on movement, sleep, and cognition. Gamma oscillations appear to participate in sensory perception, problem solving, and memory, and coherence at these frequencies may occur at cortical or thalamocortical levels. However, rather than participating in the temporal binding of sensory events, gamma band activity generated in the RAS may help stabilize coherence related to arousal, providing a stable activation state during waking, and relay such activation to the cortex. Continuous sensory input will thus induce gamma band activity in the RAS to participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our perceptions and actions. Such a role has received little attention but promises to help understand and treat a number of neurological disorders.

Bottom-up Gamma: the Pedunculopontine Nucleus and Reticular Activating System.

Gamma rhythms have been proposed to promote the feed forward or "bottom-up" flow of information from lower to higher regions in the brain during perception. On the other hand, beta rhythms have been proposed to represent feed back or "top-down" influence from higher regions to lower. The pedunculopontine nucleus (PPN) has been implicated in sleep-wake control and arousal, and is part of the reticular activating system (RAS). This review describes the properties of the cells in this nucleus. These properties are unique, and perhaps it is the particular characteristics of these cells that allow the PPN to be involved in a host of functions and disorders. The fact that all PPN neurons fire maximally at gamma band frequency regardless of electrophysiological or transmitter type, make this an unusual cell group. In other regions, for example in the cortex, cells with such a property represent only a sub-population. More importantly, the fact that this cell group's functions are related to the capacity to generate coherent activity at a preferred natural frequency, gamma band, speaks volumes about how the PPN functions. We propose that "bottom-up" gamma band influence arises in the RAS and contributes to the build-up of the background of activity necessary for preconscious awareness and gamma activity at cortical levels.

Arousal, motor control, and parkinson's disease.

This review highlights the most important discovery in the reticular activating system (RAS) in the last 10 years, the manifestation of gamma (γ) band activity in cells of the RAS, especially in the pedunculopontine nucleus (PPN), which is in charge of the high frequency states of waking and rapid eye movement sleep. This discovery is critical to understanding the modulation of movement by the RAS and how it sets the background over which we generate voluntary and triggered movements. The presence of γ band activity in the RAS is proposed to participate in the process of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. Early findings using stimulation of this region to induce arousal, and also to elicit stepping, are placed in this context. This finding also helps explain the novel use of PPN deep brain stimulation for the treatment of Parkinson's disease, although considerable work remains to be done.

Transplantation of thymus tissue in complete DiGeorge syndrome.

BACKGROUND: The DiGeorge syndrome is a congenital disorder that affects the heart, parathyroid glands, and thymus. In complete DiGeorge syndrome, patients have severely reduced T-cell function. METHODS: We treated five infants (age, one to four months) with complete DiGeorge syndrome by transplantation of cultured postnatal thymus tissue. Follow-up evaluations included immune phenotyping and proliferative studies of peripheral-blood mononuclear cells plus biopsy of the thymus allograft. Thymic production of new T cells was assessed in peripheral blood by tests for T-cell-receptor recombination excision circles, which are formed from excised DNA during the rearrangement of T-cell-receptor genes. RESULTS: After the transplantation of thymus tissue, T-cell proliferative responses to mitogens developed in four of the five patients. Two of the patients survived with restoration of immune function; three patients died from infection or abnormalities unrelated to transplantation. Biopsies of grafted thymus in the surviving patients showed normal morphologic features and active T-cell production. In three patients, donor T cells could be detected about four weeks after transplantation, although there was no evidence of graft-versus-host disease on biopsy or at autopsy. In one patient, the T-cell development within the graft was demonstrated to accompany the appearance of recently developed T cells in the periphery and coincided with the onset of normal T-cell function. In one patient, there was evidence of thymus function and CD45RA+CD62L+ T cells more than five years after transplantation. CONCLUSIONS: In some infants with profound immunodeficiency and complete DiGeorge syndrome, the transplantation of thymus tissue can restore normal immune function. Early thymus transplantation - before the development of infectious complications - may promote successful immune reconstitution.

Congenital diaphragmatic hernia survival and use of extracorporeal life support at selected level III nurseries with multimodality support.

BACKGROUND: Congenital diaphragmatic hernia (CDH) has been cited to have a mortality rate of 50%. There have been multiple studies at individual institutions demonstrating potential benefits from various strategies including extracorporeal life support (ECLS), delayed repair, and lower levels of ventilator support. There has been no multicenter survey of institutions offering these modalities to describe the current use of ECLS and survival of these infants. In addition, the relationship between the number of patients with CDH managed at an individual institution and outcome has not been evaluated. METHODS: We queried 16 level III neonatal intensive care centers on the use of ECLS and survival of infants with CDH who were treated during 2 consecutive years (1993 to 1995). Data are presented as mean +/- SEM, median, and range. RESULTS: Data were collected on 411 patients. Of these, 71% +/- 8% were outborn and 8% +/- 3% were considered nonviable. Overall survival of CDH infants was 69% +/- 4% (range, 39% to 95%). The survival rate of infants on ECLS was 55% +/- 4%, whereas survival of infants not requiring ECLS was significantly increased at 81% +/- 5% (p = 0.005). The mean rate of ECLS use was 46% +/- 2%. There was no correlation between the number of cases per year at an individual institution and overall survival, ECLS survival, or ECLS use (r = 0.341, 0.305, and 0.287, respectively). There was also no correlation between case volume at an individual institution and ECLS survival (r = 0.271). CONCLUSIONS: The current survival rate and rate of ECLS use in infants with CDH at level III neonatal intensive care units in the United States are 69% +/- 4% and 46% +/- 2%, respectively. There is no correlation between the yearly individual center experience with managing CDH and rate of ECLS use or outcome.

Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus.

Transplantation of cultured postnatal human thymus was performed in a patient with complete DiGeorge syndrome. Biopsy of the graft 3 mo after implantation revealed normal CD1+ thymocytes in thymic cortical epithelial regions and CD1- thymocytes in thymic medullary epithelial regions, respectively. HLA analysis of graft thymocyte and thymic microenvironment components demonstrated that developing thymocytes and thymic macrophages were recipient derived, while thymic epithelial components were of donor origin. The patient, who initially had no T cells and had profoundly defective T cell function, developed normal T cell responses to mitogens and Ags, tolerance to donor in a mixed lymphocyte reaction, and normal Ab titers after tetanus toxoid and pneumovax immunization. Thus, transplantation of cultured postnatal human thymic tissue in humans can form functional chimeric thymic tissue, and may provide a strategy to reconstitute the peripheral T cell pool in select congenital and acquired immune deficiency syndromes.

Jugular ligation does not increase intracranial pressure but does increase bihemispheric cerebral blood flow and metabolism.

OBJECTIVES: To answer the following questions: a) Does jugular venous ligation (simulating venovenous extracorporeal life support) alter proximal jugular venous pressure, intracranial pressure, hemispheric cerebral blood flow, or cerebral metabolism? b) Does release of ligation reverse these effects? and c) What are the comparative effects of venous ligation alone vs. venous ligation in combination with arterial ligation? DESIGN: Prospective, randomized, laboratory investigation. SETTING: Multidisciplinary laboratory setting. SUBJECTS: Sixteen swine, weighing 8.1 to 12.1 kg, 3 to 4 wks of age. INTERVENTIONS: Sixteen swine were randomly assigned to two groups, utilizing a random sequence of vessel ligation. Nine swine underwent occlusion of the right internal and external jugular veins alone (venovenous ligation) followed by release of the occlusion and then occlusion of the right common carotid artery and the right internal and external jugular veins together (venoarterial ligation). The remaining seven swine underwent venoarterial ligation, followed by release of the occlusion and then venovenous ligation. In the experimental group in which venovenous ligation was performed first, the 5, and 30-min release periods after ligation were taken to represent the effects of draining the right jugular vein during venovenous extracorporeal life support. MEASUREMENTS AND MAIN RESULTS: Data were obtained at baseline, 5, and 30 mins after each ligation/release period. Intracranial pressure, right and left internal jugular pressures/flow rates, and cerebral sinus lactate concentrations were measured. Cerebral blood flow was determined using 133Xe clearance methodology, and the cerebral metabolic rate was calculated. There were no significant differences between the ipsilateral internal jugular pressure or extracorporeal life support at 5 or 30 mins after venovenous or venoarterial ligation compared with baseline values or compared with the release of the ligation at 5 or 30 mins. There was a significant increase in right-side (44.7 +/- 2.0 vs. 38.8 +/- 2.4 mL/kg/min; p < .05) and left-side (42.9 +/- 2.3 vs. 38.7 +/- 1.9 mL/kg/min; p < .05) cerebral blood flow 5 mins after venovenous ligation when compared with baseline values. Similarly, after venoarterial ligation, there was a significant increase in right-side (44.6 +/- 2.2 vs. 38.8 +/- 2.4 mL/kg/min; p < .05) and left-side (43.9 +/- 1.5 vs. 38.7 +/- 1.9 mL/kg/min; p < .05) and cerebral blood flow. Cerebral oxygen consumption was significantly increased after venovenous (2.7 +/- 0.2 to 3.2 +/- 0.2 mL/kg/min; p < .05) and venoarterial (2.7 +/- 0.2 to 3.1 +/- 0.2 mL/kg/min; p < .05) ligation at 5 mins after ligation. This increase persisted at the 30-min period and after release of ligation. CONCLUSIONS: Ligation of the right jugular veins alone (venovenous ligation) or jugular veins and right carotid artery (venoarterial ligation) does not increase jugular venous pressures or intracranial pressure. However, this procedure does increase cerebral blood flow and cerebral oxygen consumption. These findings demonstrate that there is adequate decompression of the venous system by the cerebrovascular system and retrograde decompression during extracorporeal life support appears unwarranted.

Metabolic function of the isolated perfused rat liver in chronic sepsis.

Significant alterations of liver function have been identified in experimental sepsis including changes in protein and glucose production. The specific changes which are evident in vivo appear to depend upon the specific experimental model and probably represent the relative contribution of hepatocellular function and extrahepatic influences as well as the time course of the septic process. Relatively few studies have focused on function of the whole organ. In an effort to study intrinsic hepatic function during chronic sepsis, control and septic animals (intraabdominal abscess) were studied using the isolated perfused liver model. Basal hepatic oxygen utilization was mildly elevated compared to that in control livers and the oxygen consumption response to a metabolic load was found to be essentially identical to that in control and septic livers. Glucose and albumin production were not substantially different in these two groups. These findings suggest that alterations in liver function following the induction of sepsis may result from extra hepatic factors, since intrinsic liver function appears to be normal.

Evaluation of the Heart Smart Restaurant Program in Saskatoon and Regina, Saskatchewan.

The consumer-driven Heart Smart Restaurant Program was developed by the Heart and Stroke Foundation of Saskatchewan and the Saskatoon Community Health Unit, with the aim of improving the nutritional quality of food consumed in table-service restaurants. To participate, restaurateurs must agree to provide smoke-free seating and specific more healthful food choices upon request of the customer. The program was evaluated through telephone interviews with 999 individuals in randomly selected households in Saskatoon and Regina. While public awareness of the program was satisfactory, over half of those who knew of the program misunderstood its function, believing that more healthful choices are indicated on the menu. When choosing a restaurant, individuals are not greatly influenced by whether it is Heart Smart, but in Saskatoon, they are more likely to request a more healthful alternative in a Heart Smart restaurant than in others. Implications of these and other findings for future program development and research are discussed.

Pudendal nerve palsy complicating intramedullary nailing of the femur.

A prospective study of 106 patients who had static interlocking nailing of the shaft of the femur was performed to determine the relationship between the duration and magnitude of intraoperative traction and the development of a pudendal nerve palsy. A strain-gauge, mounted in the countertraction post, measured the magnitude of the perineal pressure over time. All nailings were performed with the patient in the supine position. Postoperatively, the patients were interviewed by one of us, who had been blinded from the results of the recordings of intraoperative pressure, for a history of erectile dysfunction and changes in labial, scrotal, or penile sensation. A light-touch sensory examination of the genitalia was performed on all patients. Ten patients (six men and four women) had a pudendal nerve palsy: nine had sensory changes only, and one complained of erectile dysfunction. The symptoms had resolved at the three-month follow-up evaluation in all patients except one man who complained of dysesthesia six months postoperatively. The patients in whom a palsy did not develop had been positioned on the fracture-table and the perineal post for an average of 2.6 hours (range, 1.4 to 5.2 hours) compared with an average of 2.8 hours (range, 2.0 to 4.3 hours) for those in whom a palsy did not develop (p = 0.15). The magnitude of the total traction forces averaged 34.9 kilogram-hours for the patients who did not have a palsy compared with 73.3 kilogram-hours for those who did (p < 0.03). Adduction of the hip, as well as manipulations for reduction of the fracture, significantly increased the traction forces.(ABSTRACT TRUNCATED AT 250 WORDS)

Pseudomembranous colitis following resection for Hirschsprung's disease.

Enterocolitis is the most common cause of significant morbidity and death in Hirschsprung's disease. Although most cases respond to nasogastric decompression, antibiotics, and colonic evacuation, some children have an unusually fulminant or protracted clinical course. Four cases are reported of pseudomembranous colitis (PMC) that developed 1 to 18 months (mean, 8 months) after definitive surgery for Hirschsprung's disease (Soave endorectal pull-though, 2; Duhamel procedure, 2). While all children presented with fever, abdominal distention, and diarrhea, indistinguishable from typical Hirschsprung's enterocolitis, the clinical course was fulminant in two cases, both of whom died of septic shock. Postmortem examination in both showed extensive colonic pseudomembranes despite identification of Clostridium difficile toxin and subsequent vancomycin therapy (initiated late in the clinical course). Two children in the series had protracted hospitalizations and eventually required diverting enterostomy despite recognition of C difficile toxin and treatment with enteral vancomycin, in one child necessitating multiple courses of antibiotic therapy. Awareness of the virulence of PMC associated with Hirschsprung's disease (even after definitive resection) should prompt submission of stool specimens from any child who presents with enterocolitis for both C difficile culture and toxin levels. On the basis of our experience it is our policy to initiate a prompt course of vancomycin by rectal lavage or nasogastric tube in all children with Hirschsprung's enterocolitis, pending culture results, in view of the significant morbidity and mortality exemplified by cases in this review.

Multiple endocrine neoplasia type II B with symptoms suggesting Hirschsprung's disease: a case report.

A 3-year-old child was referred with a tentative diagnosis of Hirschsprung's disease because of life-long constipation and "megacolon" demonstrated radiographically. Our rectal biopsy revealed hyperganglionosis suggestive of multiple endocrine neoplasia (MEN) type II B. This, in addition to an elevated serum calcitonin level, prompted surgical removal of her thyroid, which appeared grossly normal but on sectioning, contained a medullary carcinoma in each lobe. She remains disease-free 5 years later. Gastrointestinal symptoms are a significant component of the MEN type II B syndrome, and often antedate the full phenotypic expression of the syndrome and the development of potentially lethal endocrine neoplasms. On the basis of this experience, it is recommended that MEN II B be included in the differential diagnosis of chronic constipation.

Causative factors for decreased pulmonary metastasis in parenterally fed mice.

Total parenteral nutrition (TPN) with fat and/or glucose as the caloric source is associated with a decrease in pulmonary metastasis in mice bearing subcutaneously implanted Lewis lung carcinoma. Five groups of white mice bearing Lewis lung carcinoma were assigned to receive various isocaloric and isonitrogenous oral and parenteral feedings: TPN, utilizing all nonnitrogen energy from glucose; per os, utilizing all nonnitrogen calories from glucose; electrolyte, utilizing nonnitrogen calories provided from a balanced casein diet and receiving an isovolemic infusion of electrolytes in the same composition as the TPN formula; 1/4 normal saline, also consuming the casein diet and receiving an isovolemic infusion of 1/4 normal saline; and an oral casein control (CON) without infusion. Results showed that there were no significant differences in tumor volume changes or tumor doubling time among the groups. However, tumor weight was significantly lower in groups receiving the TPN solution either orally or parenterally in comparison to the oral casein control. Pulmonary metastases were significantly lower in all parenteral groups, irrespective of solution composition, compared to the CON group. Thus it appears that parenteral fluid load rather than composition of the solution is the causative factor for the decrease in pulmonary metastases.