Aging-induced alterations in EEG spectral power associated with graded force motor tasks.

BACKGROUND: It has been demonstrated that in young and healthy individuals, there is a strong association between the amplitude of EEG-derived motor activity-related cortical potential or EEG spectral power (ESP) and voluntary muscle force. This association suggests that the motor-related ESP may serve as an index of central nervous system function in controlling voluntary muscle activation Therefore, it may potentially be used as an objective marker to track changes in functional neuroplasticity due to neurological disorders, aging, and following rehabilitation therapies. To this end, the relationship between the band-specific ESP-combined spectral power of EEG oscillatory and aperiodic (noise) components-and voluntary elbow flexion (EF) force has been analyzed in elder and young individuals. METHODS: 20 young (22.6 ± 0.87 year) and 28 elderly (74.79 ± 1.37 year) participants performed EF contractions at 20%, 50%, and 80% of maximum voluntary contraction (MVC) while high-density EEG signals were recorded. Both the absolute and relative ESPs were computed for the EEG frequency bands of interest. RESULTS: The MVC force generated by the elderly was foreseeably lower than that of the young participants. Compared to young, the elderly cohort's (1) total ESP was significantly lower for the high (80% MVC) force task; (2) relative ESP in beta band was significantly elevated for the low and moderate (20% MVC and 50% MVC) force tasks; (3) absolute ESP failed to have a positive trend with force for EEG frequency bands of interest; and (4) beta-band relative ESP did not exhibit a significant decrease with increasing force levels. CONCLUSIONS: As opposed to young subjects, the beta-band relative ESP in elderly did not significantly decrease with increasing EF force values. This observation suggests the use of beta-band relative ESP as a potential biomarker for age-related motor control degeneration.

Corrigendum: EEG-based spectral analysis showing brainwave changes related to modulating progressive fatigue during a prolonged intermittent motor task.

[This corrects the article DOI: 10.3389/fnhum.2022.770053.].

Obstetric comorbidity index and the odds of general vs. neuraxial anesthesia in women undergoing cesarean delivery: a retrospective cohort study.

BACKGROUND: Maternal and fetal concerns have prompted a significant reduction in general anesthesia (GA) use for cesarean delivery (CD). The obstetric comorbidity index (OB-CMI) is a validated, dynamic composite score of comorbidities encountered in an obstetric patient. We sought to estimate the association between OB-CMI and odds of GA vs. neuraxial anesthesia (NA) use for CD. METHODS: In this single-center, retrospective cohort study conducted at a large academic hospital in the United States of America, OB-CMI was calculated on admission and every 12 h for women undergoing CD at ≥23 weeks' gestation (n=928). The CD urgency, anesthesia type, and most recent OB-CMI were extracted from the medical record. The association between OB-CMI and GA use was estimated by logistic regression, with and without adjustment for CD urgency, parity and race. RESULTS: Each one-point increase in OB-CMI was associated with a 32% (95% confidence interval [CI] 17% to 48%) increase in the odds of GA use (Model 1, area under the receiver operating characteristic curve [AUC] 0.708, 95% CI 0.610 to 0.805). The AUC improved to 0.876 (95% CI 0.815 to 0.937) with the addition of emergent CD (Model 2, P <0.001 vs. Model 1), but not parity and race (Model 3, AUC 0.880, 95% CI 0.824 to 0.935; P=0.616 vs. Model 2). CONCLUSIONS: The OB-CMI is associated with increased odds of GA vs. NA use for CD, particularly when emergent. Collected in real time, the OB-CMI may enable prophylaxis (e.g. comorbidity modification, earlier epidural catheter placement, elective CD) or preparation for GA use.

EEG-Based Spectral Analysis Showing Brainwave Changes Related to Modulating Progressive Fatigue During a Prolonged Intermittent Motor Task.

Repeatedly performing a submaximal motor task for a prolonged period of time leads to muscle fatigue comprising a central and peripheral component, which demands a gradually increasing effort. However, the brain contribution to the enhancement of effort to cope with progressing fatigue lacks a complete understanding. The intermittent motor tasks (IMTs) closely resemble many activities of daily living (ADL), thus remaining physiologically relevant to study fatigue. The scope of this study is therefore to investigate the EEG-based brain activation patterns in healthy subjects performing IMT until self-perceived exhaustion. Fourteen participants (median age 51.5 years; age range 26-72 years; 6 males) repeated elbow flexion contractions at 40% maximum voluntary contraction by following visual cues displayed on an oscilloscope screen until subjective exhaustion. Each contraction lasted ≈5 s with a 2-s rest between trials. The force, EEG, and surface EMG (from elbow joint muscles) data were simultaneously collected. After preprocessing, we selected a subset of trials at the beginning, middle, and end of the study session representing brain activities germane to mild, moderate, and severe fatigue conditions, respectively, to compare and contrast the changes in the EEG time-frequency (TF) characteristics across the conditions. The outcome of channel- and source-level TF analyses reveals that the theta, alpha, and beta power spectral densities vary in proportion to fatigue levels in cortical motor areas. We observed a statistically significant change in the band-specific spectral power in relation to the graded fatigue from both the steady- and post-contraction EEG data. The findings would enhance our understanding on the etiology and physiology of voluntary motor-action-related fatigue and provide pointers to counteract the perception of muscle weakness and lack of motor endurance associated with ADL. The study outcome would help rationalize why certain patients experience exacerbated fatigue while carrying out mundane tasks, evaluate how clinical conditions such as neurological disorders and cancer treatment alter neural mechanisms underlying fatigue in future studies, and develop therapeutic strategies for restoring the patients' ability to participate in ADL by mitigating the central and muscle fatigue.

Altered Modulation of the Movement-Related Beta Desynchronization with Force in Stroke - a Pilot Study.

Conventional therapy improves motor recovery after stroke. However, 50% of stroke survivors still suffer from a significant level of long-term upper extremity impairment. Identifying a specific biomarker whose magnitude scales with the level of force could help in the development of more effective, novel, highly targeted rehabilitation therapies such as brain stimulation or neurofeedback. Four chronic stroke participants were enrolled in this pilot study to find such a neural marker using an Independent Component Analysis (ICA)-based source analysis approach, and investigate how it has been affected by the injury. Beta band desynchronization in the ipsilesional primary motor cortex was found to be most robustly scaling with force. This activity modulation with force was found to be significantly reduced, and to plateau at higher force than that of the contralesional (unaffected) side. A rehabilitation therapy that would target such a neuromarker could have the potential to strengthen the brain-to-muscle drive and improve motor learning and recovery.Clinical Relevance- This study identifies a neural marker that scales with motor output and shows how this modulation has been affected by stroke.

Graph-theoretical analysis of EEG functional connectivity during balance perturbation in traumatic brain injury: A pilot study.

Traumatic brain injury (TBI) often results in balance impairment, increasing the risk of falls, and the chances of further injuries. However, the underlying neural mechanisms of postural control after TBI are not well understood. To this end, we conducted a pilot study to explore the neural mechanisms of unpredictable balance perturbations in 17 chronic TBI participants and 15 matched healthy controls (HC) using the EEG, MRI, and diffusion tensor imaging (DTI) data. As quantitative measures of the functional integration and segregation of the brain networks during the postural task, we computed the global graph-theoretic network measures (global efficiency and modularity) of brain functional connectivity derived from source-space EEG in different frequency bands. We observed that the TBI group showed a lower balance performance as measured by the center of pressure displacement during the task, and the Berg Balance Scale (BBS). They also showed reduced brain activation and connectivity during the balance task. Furthermore, the decrease in brain network segregation in alpha-band from baseline to task was smaller in TBI than HC. The DTI findings revealed widespread structural damage. In terms of the neural correlates, we observed a distinct role played by different frequency bands: theta-band modularity during the task was negatively correlated with the BBS in the TBI group; lower beta-band network connectivity was associated with the reduction in white matter structural integrity. Our future studies will focus on how postural training will modulate the functional brain networks in TBI.

British Dietetic Association's Obesity Specialist Group dietetic obesity management interventions in children and young people: review & clinical application.

BACKGROUND: Dietitians play a vital role in the management of childhood obesity. To support that role the Obesity Specialist Group of the British Dietetic Association commissioned a review and clinical application paper. This current paper is a summary of that review document, which is available on the BDA's website. METHODS: The initial sources of evidence were guidelines, published reviews and government guidance. Best practice advice was sought from networks including the BDA's Obesity and Paediatric Specialists groups. The original document was reviewed by a review group and members of the Obesity and Paediatric Specialist group's committees. RESULTS: The overall aim of dietetic interventions in childhood weight management should be to deliver evidence based dietetic weight management care, which helps maintain positive lifestyle changes. To support this aim the review recommends the UK BMI cut off points in setting service referral and triaging criteria. Ensuring the whole child's world is taken into account when undertaking assessment and throughout the programme process is essential. Dietitians working in this field require behavioural change skills, motivational techniques and the ability to communicate to children of differing ages and their parents. Knowledge of local child safe guarding procedures are necessary for all working in this field. Recommendations on basic and advanced skills required are specified. CONCLUSIONS: This paper was written to compliment a full review document. The complexities around case management, child protection issues and competing family motivations require dietitians trained at undergraduate and postgraduate level to deliver high quality weight management and behavioural change.

Continued neurogenesis is not a pre-requisite for regeneration of a topographic retino-tectal projection.

Electrophysiological recording demonstrated that visuo-tectal projections are topographically organised after optic nerve regeneration in aged Xenopus laevis. 3H-thymidine autoradiography confirmed previous reports [Taylor, Lack, & Easter, Eur. Journal of Neuroscience 1 (1989) 626-638] that cell division had already ceased at the retinal ciliary margin. The results demonstrate that, contrary to a previous suggestion [Holder & Clarke, Trends in Neuroscience 11 (1988) 94-99], continued neurogenesis is not a pre-requisite for the re-establishment of appropriate connections with target cells.

Modulation of cell proliferation in the embryonic retina of zebrafish (Danio rerio).

We describe light-microscopically the development of the embryonic zebrafish eye with particular attention to cell number, cell proliferation, and cell death. The period from 16 to 36 hr post fertilization (hpf) comprises two phases; during the first (16-27 hpf) the optic vesicle becomes the eye cup, and during the second (27-36 hpf) the eye cup begins to differentiate into the neural retina and pigmented epithelium. All cells in the eye primordium are proliferative prior to 28 hpf, and the length of the cell cycle has been estimated to be 10 hr at 24-28 hpf (Nawrocki, 1985). Our cell counts are consistent with that estimate at that age, but not at earlier ages. A 10-hr cell cycle predicts that the cell number should increase by 7% per hr, but during 16-24 hpf the cell number increased by only 1.5% per hr. Despite the low rate of increase, all cells labeled with bromo-deoxyuridine, so all were proliferative. We considered three possible explanations for the nearly-constant cell number in the first phase: proliferation balanced by cell emigration from the eye, proliferation balanced by cell death, and low proliferation caused by a transient prolongation of the cell cycle. We excluded the first two, and found direct support for the third. Previous examinations of the cell cycle length in vertebrate central nervous system have concluded that it increases monotonically, in contrast to the modulation that we have shown. Modulation of the cell cycle length is well-known in flies, but it is generally effected by a prolonged arrest at one phase, in contrast to the general deceleration that we have shown.

The morphogenesis of the zebrafish eye, including a fate map of the optic vesicle.

We have examined the morphogenesis of the zebrafish eye, from the flat optic vesicle at 16 hours post fertilization (hpf) to the functional hemispheric eye at 72 hpf. We have produced three-dimensional reconstructions from semithin sections, measured volumes and areas, and produced a fate map by labeling clusters of cells at 14-15 hpf and finding them in the 24 hpf eye cup. Both volume and area increased sevenfold, with different schedules. Initially (16-33 hpf), area increased but volume remained constant; later (33-72 hpf) both increased. When the volume remained constant, the presumptive pigmented epithelium (PE) shrank and the presumptive neural retina (NR) enlarged. The fate map revealed that during 14-24 hpf cells changed layers, moving from the PE into the NR, probably through involution around the margin of the eye. The transformation of the flat epithelial layers of the vesicle into their cup-shaped counterparts in the eye was also accompanied by cellular rearrangements; most cells in a cluster labeled in the vesicle remained neighbors in the eye cup, but occasionally they were separated widely. This description of normal zebrafish eye development provides explanations for some mutant phenotypes and for the effects of altered retinoic acid.

Quality of life related to fear of falling and hip fracture in older women: a time trade off study.

OBJECTIVE: To estimate the utility (preference for health) associated with hip fracture and fear of falling among older women. DESIGN: Quality of life survey with the time trade off technique. The technique derives an estimate of preference for health states by finding the point at which respondents show no preference between a longer but lower quality of life and a shorter time in full health. SETTING: A randomised trial of external hip protectors for older women at risk of hip fracture. PARTICIPANTS: 194 women aged >/= 75 years enrolled in the randomised controlled trial or who were eligible for the trial but refused completed a quality of life interview face to face. OUTCOME MEASURES: Respondents were asked to rate their own health by using the Euroqol instrument and then rate three health states (fear of falling, a "good" hip fracture, and a "bad" hip fracture) by using time trade off technique. RESULTS: On an interval scale between 0 (death) and 1 (full health), a "bad" hip fracture (which results in admission to a nursing home) was valued at 0.05; a "good" hip fracture (maintaining independent living in the community) 0.31, and fear of falling 0.67. Of women surveyed, 80% would rather be dead (utility=0) than experience the loss of independence and quality of life that results from a bad hip fracture and subsequent admission to a nursing home. The differences in mean utility weights between the trial groups and the refusers were not significant. A test-retest study on 36 women found that the results were reliable with correlation coefficients within classes ranging from 0.61 to 0.88. CONCLUSIONS: Among older women who have exceeded average life expectancy, quality of life is profoundly threatened by falls and hip fractures. Older women place a very high marginal value on their health. Any loss of ability to live independently in the community has a considerable detrimental effect on their quality of life.

Characteristics of families who attend free vaccine fairs.

OBJECTIVE: To determine the health care resources and perceived barriers to care of families attending free vaccine fairs. DESIGN: A cross-sectional survey. SETTING: Twelve free vaccine fairs in Denver, Colorado, in 1994. PARTICIPANTS: A total of 533 consecutive parents or guardians of children receiving vaccine at the fairs. Interventions. None. MEASUREMENTS/RESULTS: Survey respondents reported that their children received regular health care through a private physician or health maintenance organization (HMO) (47%), a public clinic (20%), or a hospital-based clinic (14%); 18% had no regular site for health care. Twenty-seven percent of the families carried private insurance, although less than half of these plans covered children's vaccines: 9% were enrolled in an HMO or a preferred provider organization and 13% had Medicaid, whereas 50% had no health insurance. Families who received primary care at a private physician's office (OR: 1.7; 95% CI: 1.01-2.7) and those with no regular site for health care (OR: 2.0; 95% CI: 1.01-4.0) were more likely than those who went to a public clinic or hospital clinic to report free vaccine as the most important reason for attending a vaccine fair. Conversely, families who received well-child care at a hospital clinic were more likely to identify no appointment needed as the most important reason (OR: 2.7; 95% CI: 1. 4-5.1). Families with private health insurance (OR: 2.3; 95% CI: 1. 05-4.0) or no health insurance (OR: 2.3; 95% CI: 1.1-4.6) were more likely to identify free vaccine as the most important reason for attending a vaccine fair, whereas those enrolled in an HMO or preferred provider organization identified convenient time as the most important reason (OR: 3.2; 95% CI: 1.2-8.3). Families with Medicaid (OR: 3.2; 95% CI: 1.3-8.3) or with no insurance (OR: 2.1; 95% CI: 1.02-4.6) were more likely than were those with private insurance to identify no appointment needed as the most important reason for attending a vaccine fair. CONCLUSIONS: Most families attending free vaccine fairs have a regular source of health care. For families with private health insurance or with no health insurance, the availability of free vaccine is the major reason to bring their children to a vaccine fair, whereas for families whose insurance routinely covers the cost of childhood vaccine (HMO, Medicaid), convenience is the major determinant.

Neurogenesis in the visual system of embryonic and adult zebrafish (Danio rerio). off.

The zebrafish has recently assumed a central position in the study of vertebrate development. Numerous studies of other fish have shown that their central nervous systems, and especially their visual systems, continue to add new neurons throughout life, which is probably related to their abilities to regenerate axons and whole nervous tissue. Retinal neurogenesis had not been examined in adult zebrafish, and two reports concluded that the optic tectum ceased neurogenesis early in life, so the question arose whether the zebrafish was anomalous in this regard. We labeled embryonic (24- and 48-h postfertilization) and adult zebrafish with the thymidine analog, bromo-deoxyuridine, and, after short and long survivals, examined the retina and brain for labeled cells. They were abundant in both the optic tectum and the retina. Although the rate of retinal growth slows considerably between embryonic and adult stages, the patterns of neurogenesis in both the embryo and the adult are similar to those described in other fish, so these "fish-specific" features of general interest can justifiably be studied in zebrafish.

Retinal neurogenesis: the formation of the initial central patch of postmitotic cells.

We have investigated the relationship between the birthdate and the onset of differentiation of neurons in the embryonic zebrafish neural retina. Birthdates were established by a single injection of bromodeoxyuridine into embryos of closely spaced ages. Differentiation was revealed in the same embryos with a neuron-specific antibody, zn12. The first bromodeoxyuridine-negative (postmitotic) cells occupied the ganglion cell layer of ventronasal retina, where they formed a small cluster of 10 cells or less that included the first zn12-positive cells (neurons). New cells were recruited to both populations (bromodeoxyuridine-negative and zn12-positive) along the same front, similar to the unfolding of a fan, to produce a circular central patch of hundreds of cells in the ganglion cell layer about 9 h later. Thus the formation of this central patch, previously considered as the start of retinal neurogenesis, was actually a secondary event, with a developmental history of its own. The first neurons outside the ganglion cell layer also appeared in ventronasal retina, indicating that the ventronasal region was the site of initiation of all retinal neurogenesis. Within a column (a small cluster of neuroepithelial cells), postmitotic cells appeared first in the ganglion cell layer, then the inner nuclear layer, and then the outer nuclear layer, so cell birthday and cell fate were correlated within a column. The terminal mitoses occurred in three bursts separated by two 10-h intervals during which proliferation continued without terminal mitoses.

The development of eye movements in the zebrafish (Danio rerio).

We investigated the development of oculomotor activity in zebrafish embryos and larvae of ages 48-96 hrs postfertilization (hpf). The optokinetic response (OKR: smooth tracking movements evoked by a rotating striped drum) improved steadily after its onset at 73 hpf, and by 96 hpf had a achieved a gain (eye velocity/drum velocity) of 0.9, comparable to adult performance. Reset movements (the fast phase of optokinetic nystagmus) developed over 75-81 hpf. The vestibuloocular reflex (VOR: compensatory eye movements evoked by passive rotation of the head) developed over 74-81 hpf, and the associated reset movements, over 76-81 hpf. The VOR was qualitatively normal in dark-reared fish, which excludes an essential role for visual experience in its early development. Spontaneous saccadic movements (the fast shift of eye position) appeared between 81 and 96 hpf, and at 96 hpf had maximum velocities that were comparable to adults. These results are compared to, and found to be incompatible with, two earlier ideas of motor development: behavioral "differentiation" and "encephalization."

An assessment of rat photoreceptor sensitivity to mitochondrial blockade.

PURPOSE: To report results of functional, biochemical and structural studies of photoreceptor mitochondria in isolated rat retinas under conditions of mitochondrial inhibition. METHODS: Dark-adapted rat retinas were incubated in a modified Ringer's bicarbonate medium under aerobic and anaerobic conditions. Several different procedures were used to inhibit mitochondrial function; N2, 0.01 mM antimycin A, and 1 and 10 mM potassium cyanide (KCN). Measurements were made of lactic acid production, retinal adenosine triphosphate (ATP) content, and receptor potentials. Morphology of the inner segment mitochondria was examined by electron microscopy. RESULTS: In the presence of N2, 0.01 mM antimycin, or 1 mM KCN, lactic acid production was linear throughout the 60- minute period; and the rate was similar for each condition. Retinal ATP content and the amplitude of the receptor potential were also maintained at high levels after short-term incubations with either N2, antimycin A, or 1 mM KCN. In contrast, use of 10 mM KCN produced an entirely different set of results. These effects were studied both at the alkaline pH (8.9) found when this concentration of KCN was simply added to bicarbonate-buffered media and at the normal pH (after readjustment) of 7.4. With 10 mM KCN (pH 8.9), retinal lactate production was severely depressed, retinal ATP content was nearly depleted within 5 to 10 minutes, and the amplitude of the receptor potential rapidly declined to a low level. The deleterious effects of 10 mM KCN on these parameters were lessened to varying degrees when pH was readjusted to 7.4. Electron microscopic observations of rat rod inner segments indicated generally excellent survival of these organelles after incubation with either N2, antimycin A, or 1 mM KCN in comparison with their appearance under oxygenated conditions. However, the inner segments were significantly disrupted after incubation of retinas with 10 mM KCN. CONCLUSIONS: Findings suggest that the loss of the receptor potential and depletion of ATP observed with minutes after exposing isolated rat retinas to media containing 10 mM KCN results from the inhibition of both respiration and glycolysis by this high concentration of KCN. In contrast, when conditions are chosen so that only respiration is impaired (as with N2, antimycin A, or 1 mM KCN) photoreceptor cells are resistant to short-term episodes of mitochondrial inhibition, principally because the upregulation of glycolysis generates sufficient ATP to compensate reasonably well for the loss in mitochondrially produced ATP.

Pax-6 functions in boundary formation and axon guidance in the embryonic mouse forebrain.

The Pax-6 gene encodes a transcription factor that is expressed in regionally restricted patterns in the developing brain and eye. Here we describe Pax-6 expression in the early forebrain (prosencephalon) on embryonic day 9.5 (E9.5) to E10.5 using both whole-mount in situ hybridization and antibody labeling. We find close correlations between Pax-6+ domains and initial neural patterning, and identify corresponding defects in embryos homozygous for the Pax-6 allele, Small eye (Sey). Pax-6 expression defines the prosencephalon-mesencephalon boundary, and mutant embryos lack this morphological boundary. Markers of the caudal prosencephalon are lost (Pax-6, Lim-1, Gsh-1) and a marker for mesencephalon is expanded rostrally into the prosencephalon (Dbx). We conclude that the caudal prosencephalon (prosomere 1) is at least partially transformed to a mesencephalic fate. This transformation results in a specific deficit of posterior commissure axons. Sey/Sey embryos also exhibit an axon pathfinding defect specific to the first longitudinal tract in the prosencephalon (tpoc, tract of the postoptic commissure). In wild type, tpoc axons fan out upon coming in contact with a superficial patch of Pax-6+ neuron cell bodies. In the mutant, the tpoc axons have normal initial projections, but make dramatic errors where they contact the neuron cell bodies, and fail to pioneer this first tract. Thus Pax-6 is required for local navigational information used by axons passing through its domain of expression. We conclude that Pax-6 plays multiple roles in forebrain patterning, including boundary formation, regional patterning, neuron specification and axon guidance.

The development of vision in the zebrafish (Danio rerio).

We studied the development and maturation of the visual system by determining when zebrafish begin to see and to move their eyes. This information was correlated with the time courses of the development of the retina, the retinofugal projection, the retinal image, and the extraocular muscles, to obtain an integrated picture of early visual development. Two visual behaviors were monitored over 48-96 hr postfertilization (hpf). The startle response (body twitch) was evoked by an abrupt decrease in light intensity. The optokinetic response (tracking eye movements) was evoked by rotation of a striped drum. Visually evoked startle developed over 68-79 hpf, more than 20 hr after the onset of a touch-evoked startle. It was not seen in eyeless fish, excluding a role for nonretinal light senses. Tracking eye movements developed over 73-80 hpf. They were always in the direction of drum rotation, even when the fish had been light deprived from blastula stage, ruling out a "trial and error" period of learning to track the drum. The image formed by the ocular lens was examined in intact fish made transparent by suppressing the formation of melanin. The eye was initially far sighted and gradually improved, so that by 72 hpf the image plane coincided with the photoreceptor layer. The extraocular muscles assumed their adult configuration between 66 and 72 hpf. Thus, the retinal image and functional extraocular muscles appeared nearly simultaneously with the onset of tracking eye movements and probably represent the last events in the construction of this behavior.

Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families.

OBJECTIVE: This study was an attempt to replicate evidence for a vulnerability locus for schizophrenia and associated disorders in the 8p22-21 region reported by Pulver and colleagues. METHOD: The linkage sample of the Irish Study of High-Density Schizophrenia Families consists of 265 multiplex families containing 1,408 individuals. Fifteen markers covering 30 centimorgans on chromosome 8p were tested. Three statistical methods were used: two-point and multipoint heterogeneity lod scores and a multipoint nonparametric test. RESULTS: According to two-point heterogeneity lod scores, the strongest evidence for linkage was found for markers D8S1731 (maximum lod score = 2.00), D8S1715 (maximum lod score = 2.52), and D8S133 (maximum lod score = 2.08) by assuming a phenotypic definition of all psychiatric illness and a range of genetic models. According to multipoint heterogeneity lod scores, the strongest evidence for linkage (maximum lod score = 2.34), found by using a dominant genetic model and a broad definition of the schizophrenia spectrum, extended over a 10-cM region between markers D8S1715 and D8S1739. Multipoint nonparametric linkage found the strongest evidence (maximum z = 2.51) over a broader region when either a diagnosis of core schizophrenia or a narrow definition of the schizophrenia spectrum was used. This putative vulnerability locus was segregating in 10%-25% of the families studied. CONCLUSIONS: This study supports the existence of a vulnerability locus for schizophrenia on chromosome 8p. In this sample, this locus appears to influence the risk of illness in only a modest proportion of families and predisposes to a range of schizophrenia spectrum and possibly nonspectrum disorders.