Discovering schizophrenia endophenotypes in randomly ascertained pedigrees.

BACKGROUND: Although case-control approaches are beginning to disentangle schizophrenia's complex polygenic burden, other methods will likely be necessary to fully identify and characterize risk genes. Endophenotypes, traits genetically correlated with an illness, can help characterize the impact of risk genes by providing genetically relevant traits that are more tractable than the behavioral symptoms that classify mental illness. Here, we present an analytic approach for discovering and empirically validating endophenotypes in extended pedigrees with very few affected individuals. Our approach indexes each family member's risk as a function of shared genetic kinship with an affected individual, often referred to as the coefficient of relatedness. To demonstrate the utility of this approach, we search for neurocognitive and neuroanatomic endophenotypes for schizophrenia in large unselected multigenerational pedigrees. METHODS: A fixed-effects test within the variance component framework was performed on neurocognitive and cortical surface area traits in 1606 Mexican-American individuals from large, randomly ascertained extended pedigrees who participated in the Genetics of Brain Structure and Function study. As affecteds were excluded from analyses, results were not influenced by disease state or medication usage. RESULTS: Despite having sampled just 6 individuals with schizophrenia, our sample provided 233 individuals at various levels of genetic risk for the disorder. We identified three neurocognitive measures (digit-symbol substitution, facial memory, and emotion recognition) and six medial temporal and prefrontal cortical surfaces associated with liability for schizophrenia. CONCLUSIONS: With our novel analytic approach, one can discover and rank endophenotypes for schizophrenia, or any heritable disease, in randomly ascertained pedigrees.

Craniofacial trauma as a clinical marker of seizures in a baboon colony.

Baboons provide a natural model of epilepsy. However, spontaneous seizures are usually sporadic, brief, and may not be observed. We hypothesized that various types of craniofacial trauma (CFT) may serve as reliable markers for epilepsy. We evaluated the type, demographics, and clinical significance of CFT in a large baboon colony. CFT was categorized according to somatotopic location, propensity to recur, and association with witnessed seizures or abnormal EEG findings. We divided the baboons with CFT into 2 groups: those with known histories of seizures (CFT+Sz, n = 176) and those without seizure histories (CFTonly; n = 515). In CFT+Sz baboons, the 568 injuries identified included periorbital (57%), scalp (27%), muzzle (12%), and facial (4%) injuries; multiple somatotopic locations or body parts were affected in 21 baboons. The most common CFT injuries associated with seizures were periorbital and scalp lesions (43% for each region). Compared with those in CFTonly animals, EEG abnormalities, including interictal epileptic discharges (IED) and photosensitivity were more prevalent in the CFT+Sz group, particularly among baboons with periorbital or scalp injuries. Compared with CFT+Sz animals, CFTonly baboons tended to have later onset and less frequent recurrence of CFT but higher prevalence of muzzle and tooth injuries. IED and photosensitivity were less prevalent in the CFTonly than the CFT+Sz group, with periorbital injuries carrying the highest and muzzle injuries the lowest association with IED or photosensitivity in both groups. Therefore, CFT in general and periorbital injuries in particular may be markers for seizures in baboons.

Electroclinical phenotypes in a pedigreed baboon colony.

This is the first large-scale epidemiological study evaluating the prevalence of interictal epileptic discharges (IEDs) and photosensitivity (PS) recorded by scalp EEG in a natural nonhuman-primate model of photosensitive, generalized epilepsy. Scalp EEG was used to characterize electroclinical phenotypes in a large baboon pedigree housed at the Southwest National Primate Research Center at the Texas Biomedical Research Institute (Texas Biomed) based upon IEDs and photosensitivity. Scalp EEG studies including intermittent light stimulation (ILS) were performed in 671 baboons. Clinical histories were available for 531 (79%) of the animals. The EEG studies lasted 53 (±11) min, during which the baboons were lightly sedated with intramuscular ketamine doses of 5.6 (±0.8) mg. The animals were further classified according to electroclinical phenotypes recorded by scalp EEG: presence or absence of IEDs, seizures and photoparoxysmal or photoconvulsive responses. Effects of age, gender, and species on EEG phenotypes were compared using (Chi-square, two-sided, α<0.05). Sensitivity and specificity of IEDs and photosensitivity to detect a history of seizures was calculated. Generalized IEDs and photosensitivity were identified in 324 (49%) and 156 (23%) pedigreed baboons, respectively. Only photosensitivity was associated with gender, significantly increased in males. Otherwise, while IEDs were marginally more prevalent among males, there were no other significant associations of IEDs or photosensitivity with age or subspecies. Photosensitivity was significantly associated with IEDs, with demonstrating a possible association with gender and subspecies. Of 531 baboons with histories of clinical events, 91 (17%) had witnessed seizures and 269 (51%) were asymptomatic. IEDs demonstrated sensitivity and specificity of 62% and 57%, and photosensitivity of 40% and 83%, for prediction of seizures, respectively. While these EEG findings mirror the high prevalence of seizures in the colony, the sensitivity and specificity of scalp EEG may have been affected by ketamine's ability to lower the threshold for IEDs and seizures, particularly in animals predisposed to epilepsy. Photosensitivity provides a specific biological marker for epilepsy in future epidemiological, genetic, behavioral and histopathological studies.

A kernel of truth: statistical advances in polygenic variance component models for complex human pedigrees.

Statistical genetic analysis of quantitative traits in large pedigrees is a formidable computational task due to the necessity of taking the nonindependence among relatives into account. With the growing awareness that rare sequence variants may be important in human quantitative variation, heritability and association study designs involving large pedigrees will increase in frequency due to the greater chance of observing multiple copies of rare variants among related individuals. Therefore, it is important to have statistical genetic test procedures that utilize all available information for extracting evidence regarding genetic association. Optimal testing for marker/phenotype association involves the exact calculation of the likelihood ratio statistic which requires the repeated inversion of potentially large matrices. In a whole genome sequence association context, such computation may be prohibitive. Toward this end, we have developed a rapid and efficient eigen simplification of the likelihood that makes analysis of family data commensurate with the analysis of a comparable sample of unrelated individuals. Our theoretical results which are based on a spectral representation of the likelihood yield simple exact expressions for the expected likelihood ratio test statistic (ELRT) for pedigrees of arbitrary size and complexity. For heritability, the ELRT is where h2 and λgi are, respectively, the heritability and eigenvalues of the pedigree-derived genetic relationship kernel (GRK). For association analysis of sequence variants, the ELRT is given by where ht2, hq2, and hr2 are the total, quantitative trait nucleotide, and residual heritabilities, respectively. Using these results, fast and accurate analytical power analyses are possible, eliminating the need for computer simulation. Additional benefits of eigen simplification include a simple method for calculation of the exact distribution of the ELRT under the null hypothesis which turns out to differ from that expected under the usual asymptotic theory. Further, when combined with the use of empirical GRKs-estimated over a large number of genetic markers-our theory reveals potential problems associated with nonpositive semidefinite kernels. These procedures are being added to our general statistical genetic computer package, SOLAR.

Baboon model of generalized epilepsy: continuous intracranial video-EEG monitoring with subdural electrodes.

The baboon provides a natural non-human primate model for photosensitive, generalized epilepsy. This study describes an implantation procedure for the placement of subdural grid and strip electrodes for continuous video-EEG monitoring in the epileptic baboon to evaluate the generation and propagation of ictal and interictal epileptic discharges. Subdural grid, strip and depth electrodes were implanted in six baboons, targeting brain regions that were activated in functional neuroimaging studies during photoparoxysmal responses. The baboons were monitored with continuous video-EEG monitoring for 2-21 (mean 9) days. Although the animals were tethered, the EEG signal was transmitted wirelessly to optimize their mobility. Spontaneous seizures, interictal epileptic discharges (IEDs), and responses to intermittent light stimulation (ILS) were assessed. Due to cortical injuries related to the electrode implantation and their displacement, the procedure was modified. Habitual myoclonic and generalized tonic-clonic seizures were recorded in three baboons, all associated with a generalized ictal discharge, but were triggered multiregionally, in the frontal, parietal and occipital cortices. IEDs were similarly expressed multiregionally, and responsible for triggering most generalized spike-and-wave discharges. Generalized photoparoxysmal responses were activated only in one baboon, while driving responses recorded in all three photosensitive baboons were 2.5 times the stimulus rate. In contrast to previous intracranial investigations in this model, generalized ictal and interictal epileptic discharges were triggered by parietal and occipital, in addition to the frontocentral cortices. Furthermore, targeted visual areas responded differently to ILS in photosensitive than nonphotosensitive baboons, but further studies are required before mechanisms can be implicated for ILS-induced activation of the epileptic networks.

Epidemiology and characterization of seizures in a pedigreed baboon colony.

This study evaluated the incidence, prevalence, and clinical features of seizures in a pedigreed captive colony of baboons. The association of seizures with subspecies, age, sex, and various clinical features was assessed. Records for 1527 captive, pedigreed baboons were reviewed, and 3389 events were identified in 1098 baboons. Of these events, 1537 (45%) represented witnessed seizures, whereas the remaining 1852 presented with craniofacial trauma or episodic changes in behavior that were suggestive, but not diagnostic, of seizure activity. Seizures were generalized myoclonic or tonic-clonic, with two thirds of the events witnessed in the morning. Seizure onset occurred in adolescence (age, 5 y), with an average of 3 seizures in a lifetime. The incidence and prevalence of seizures were 2.5% and 26%, respectively, whereas the prevalence of recurrent seizures (that is, epilepsy) was 15%. Seizures were more prevalent in male baboons, which tended to present with earlier onset and more seizures over a lifetime than did female baboons. Seizures were equally distributed between the subspecies; age of onset and seizure recurrences did not differ significantly between subspecies. Clinical features including age of onset, characteristics, and diurnal presentation of seizures in baboons suggested similarities to juvenile myoclonic epilepsy in humans. Facial trauma may be useful marker for epilepsy in baboons, but its specificity should be characterized.

Systems genetics of the nuclear factor-κB signal transduction network. I. Detection of several quantitative trait loci potentially relevant to aging.

A theory of aging holds that senescence is caused by a dysregulated nuclear factor kappa B (NF-κB) signal transduction network (STN). We adopted a systems genetics approach in our study of the NF-κB STN. Ingenuity Pathways Analysis (IPA) was used to identify gene/gene product interactions between NF-κB and the genes in our transcriptional profiling array. Principal components factor analysis (PCFA) was performed on a sub-network of 19 genes, including two initiators of the toll-like receptor (TLR) pathway, myeloid differentiation primary response gene (88) (MyD88) and TIR (Toll/interleukin-1 receptor)-domain-containing adapter-inducing interferon-ß (TRIF). TLR pathways are either MyD88-dependent or TRIF-dependent. Therefore, we also performed PCFA on a subset excluding the MyD88 transcript, and on another subset excluding two TRIF transcripts. Using linkage analysis we found that each set gave rise to at least one factor with a logarithm of the odds (LOD) score greater than 3, two on chromosome 15 at 15q12 and 15q22.2, and another two on chromosome 17 at 17p13.3 and 17q25.3. We also found several suggestive signals (2

Inferred relatedness and heritability in malaria parasites.

Malaria parasites vary in phenotypic traits of biomedical or biological interest such as growth rate, virulence, sex ratio and drug resistance, and there is considerable interest in identifying the genes that underlie this variation. An important first step is to determine trait heritability (H(2)). We evaluate two approaches to measuring H(2) in natural parasite populations using relatedness inferred from genetic marker data. We collected single-clone Plasmodium falciparum infections from 185 patients from the Thailand-Burma border, monitored parasite clearance following treatment with artemisinin combination therapy (ACT), measured resistance to six antimalarial drugs and genotyped parasites using 335 microsatellites. We found strong relatedness structure. There were 27 groups of two to eight clonally identical (CI) parasites, and 74 per cent of parasites showed significant relatedness to one or more other parasites. Initially, we used matrices of allele sharing and variance components (VC) methods to estimate H(2). Inhibitory concentrations (IC(50)) for six drugs showed significant H(2) (0.24 to 0.79, p = 0.06 to 2.85 x 10(-9)), demonstrating that this study design has adequate power. However, a phenotype of current interest--parasite clearance following ACT--showed no detectable heritability (H(2) = 0-0.09, ns) in this population. The existence of CI parasites allows the use of a simple ANOVA approach for quantifying H(2), analogous to that used in human twin studies. This gave similar results to the VC method and requires considerably less genotyping information. We conclude (i) that H(2) can be effectively measured in malaria parasite populations using minimal genotype data, allowing rational design of genome-wide association studies; and (ii) while drug response (IC(50)) shows significant H(2), parasite clearance following ACT was not heritable in the population studied.

High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia.

In western Cambodia, malaria parasites clear slowly from the blood after treatment with artemisinin derivatives, but it is unclear whether this results from parasite, host, or other factors specific to this population. We measured heritability of clearance rate by evaluating patients infected with identical or nonidentical parasite genotypes, using methods analogous to human twin studies. A substantial proportion (56%-58%) of the variation in clearance rate is explained by parasite genetics. This has 2 important implications: (1) selection with artemisinin derivatives will tend to drive resistance spread and (2) because heritability is high, the genes underlying parasite clearance rate may be identified by genome-wide association.

Polymerase chain reaction detection of Trypanosoma cruzi in Macaca fascicularis using archived tissues.

This study describes conventional and real-time polymerase chain reaction (PCR) methods developed to detect and quantify Trypanosoma cruzi DNA in cynomolgus monkeys (Macaca fascicularis) using formalin-fixed paraffin-embedded blocks archived for periods of up to 6 years. The highest concentration of T. cruzi DNA was found in the myocardium, urinary bladder, stomach, lymph node, adrenal gland, and colon. The concentration of T. cruzi DNA detected in cardiac tissues was 10-100-fold greater than found elsewhere; the mean concentrations of T. cruzi DNA in non-cardiac tissues were otherwise comparable. Trypanosoma cruzi DNA was amplified from cerebrum but not cerebellum or kidney. Successful use of DNA from formalin-fixed, paraffin-embedded blocks is important because most pathology laboratories routinely archive wax blocks. This archived resource can be used for further studies on the prevalence of this disease.

Mortality in captive baboons with seizures: a new model for SUDEP?

Because the baboon is a model of primary generalized epilepsy, we were interested in mortality of captive animals with a history of witnessed seizures. Causes of natural death were investigated in 46 seizure baboons (SZ) and 78 nonepileptic controls (CTL), all of which underwent a complete pathologic examination at the Southwest Foundation for Biomedical Research (SFBR) in San Antonio. SZ animals died at a younger age than the control baboons (p < 0.001). Almost all epileptic baboons that died suddenly without an apparent cause (SZ-UKN), had pulmonary congestion or edema without evidence of trauma, systemic illness, or heart disease, compared to nine controls (12%) (p < 0.001), most of which demonstrated evidence of a concurrent illness. Serosanguineous bronchial secretions were found in 15 SZ-UKN baboons (58%), but in only three controls (4%) (p < 0.001). Chronic multifocal fibrotic changes in myocardium were noted in only three (12%) of SZ-UKN baboons and one control baboon. Based upon these results, untreated seizures appear to reduce the life expectancy of captive baboons. Sudden unexpected death in epilepsy (SUDEP) may be a common cause of natural death in epileptic baboons.

Spontaneous heart disease in the adult chimpanzee (Pan troglodytes).

BACKGROUND: A high incidence of heart disease, especially idiopathic cardiomyopathy (IC), is seen in chimpanzees (Pan troglodytes). METHODS: We reviewed clinical records and necropsy reports of 87 adult chimpanzees for possible causes of heart disease/IC. We examined age, sex, cause of death, weight, diet, environment, infectious diseases, experimental uses and clinical pathology. RESULTS: The overall prevalence of heart disease in chimpanzees was 67.81%; the prevalence of IC was 51.72%. The prevalence of IC was significantly higher in males (60.32%) than that in females (29.17%, P = 0.009). The prevalence of other heart disease was higher in females (25%) than that in males (12.70%, P = 0.165). Heart failure occurred in 47.13% of chimpanzees. Heart disease was the primary cause of death in 34.49% of chimpanzees; 29.88% died of unknown causes. CONCLUSIONS: We found no evidence that diet, environment, viral agents, experimental use or disease exposure contributed to the deaths resulting from IC in chimpanzees.

Natural Chagas disease in four baboons.

BACKGROUND: Chagas disease is common in Central and South America and the southern United States. The causative agent is Trypanosoma cruzi (order Kinetoplastida, family Trypanosomatidae), a kinetoplastid protozoan parasite of humans and other vertebrates. It is a serious public health issue and the leading cause of heart disease and cardiovascular death in Central and South America. In 1984, a colony baboon was discovered to be infected with T. cruzi. METHODS: As the initial diagnosis was made by microscopic observation of the amastigote forms of T. cruzi in myocardial fibers, T. cruzi amastigotes have been identified in three additional baboons. RESULTS: The primary findings were similar in all four baboons and were congestive heart failure with edema of dependent areas, hydrothorax, hydropericardium, and multifocal to diffuse lymphoplasmacytic myocarditis. CONCLUSIONS: A baboon animal model of Chagas disease could contribute significantly to the development of therapies for the disease in humans.

"Resting" CBF in the epileptic baboon: correlation with ketamine dose and interictal epileptic discharges.

BACKGROUND: Photosensitive epileptic (SZ) baboons demonstrate different cerebral blood flow (CBF) activation patterns from asymptomatic controls (CTL) during intermittent light stimulation (ILS). This study compares "resting" CBF between PS and CTL animals, and CBF correlations with ketamine dose and interictal epileptic discharges (IEDs) between PS and CTL animals. METHODS: Continuous intravenous ketamine was administered to eight PS and eight CTL baboons (matched for gender and weight), and maintained at subanesthetic doses (4.8-14.6 mg/kg/hr). Three resting H(2)(15)O-PET studies were attempted in each animal (CTI/Siemens HR+ scanner). Images were acquired in 3D mode (63 contiguous slices, 2.4mm thickness). PET images were co-registered with MRI images (3T Siemens Trio, T1-weighted 3D Turboflash sequence, TE/TR/TI=3.04/2100/785 ms, flip angle=13 degrees ). EEG was used to monitor depth of sedation and for quantification of IED rates. Regional CBF was compared between PS and CTL groups and correlations were analyzed for ketamine dose and IED rates. RESULTS: When subsets of animals of either group, receiving similar doses of ketamine were compared, PS animals demonstrated relative CBF increases in the occipital lobes and decreases in the frontal lobes. Correlation analyses with ketamine dose confirmed the frontal and occipital lobe changes in the PS animals. The negative correlations of CBF with ketamine dose and IED rate overlapped frontally. While frontal lobe CBF was also negatively correlated with IED rate, positive correlations were found in the parietal lobe. CONCLUSIONS: "Resting" CBF differs between PS and CTL baboons. Correlation analyses of CBF and ketamine dose reveal that occipital lobe CBF increases and frontal lobe in PS animals are driven by ketamine. While frontal lobe CBF decreases may be related to ketamine's propensity to activate IEDs, positive CBF correlations with IED rate suggest involvement of the parietal lobes in their generation.

Trypanosoma cruzi in non-human primates with a history of stillbirths: a retrospective study (Papio hamadryas spp.) and case report (Macaca fascicularis).

BACKGROUND: Congenital transmission of Trypanosoma cruzi has been described in humans and experimental work has been conducted with mice, but not with non-human primates (NHPs). METHODS: We conducted a retrospective study of female baboons (Papio hamadryas spp.) naturally seropositive or seronegative for T. cruzi with history of fetal loss, and we report a stillbirth in a cynomolgus macaque (Macaca fascicularis) with placental T. cruzi amastigotes. RESULTS: There were no differences in menstrual cycle parameters and the number of fetal losses between seropositive and seronegative baboons with history of fetal loss. The amount of parasite DNA detected using quantitative polymerase chain reaction (Q-PCR) in M. fascicularis placenta was within the range detected in infected baboon tissues. CONCLUSIONS: There is no evidence that chronic maternal T. cruzi infection causes fetal loss in baboons. Q-PCR is a useful diagnostic tool to study archived NHP placentas.

Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels.

BACKGROUND: High-density lipoprotein cholesterol (HDL) levels are a major risk factor for cardiovascular disease. Previously we identified a quantitative trait locus on baboon chromosome 18 that regulates HDL. From positional cloning studies and expression studies, we identified the endothelial lipase gene (LIPG) as the primary candidate gene for the quantitative trait locus. The mechanism by which LIPG variation influences HDL levels has not been determined. METHODS AND RESULTS: We identified 164 LIPG polymorphisms in a panel of sibling baboons discordant for HDL1 and genotyped putative regulatory polymorphisms in a population of 951 pedigreed baboons. With the use of quantitative trait nucleotide analysis we identified 3 polymorphisms in the LIPG promoter associated with variation in serum HDL1 levels. In addition, we demonstrated that these 3 polymorphisms affect LIPG promoter activity in vitro. In silico analysis was used to identify putative transcription factors that differentially bind the functional promoter polymorphisms. CONCLUSIONS: These results reveal LIPG variants that specifically contribute to HDL1 levels and demonstrate mechanisms by which these polymorphisms may regulate LIPG promoter activity. Results from the present study provide a mechanism, namely variation in LIPG promoter activity possibly caused by altered transcription factor binding, by which LIPG variation affects HDL levels.

A locus on chromosome 10 influences C-reactive protein levels in two independent populations.

High sensitivity C-reactive protein (hsCRP) is an independent risk factor for cardiovascular disease, such as stroke or coronary artery disease. Genetic factors influence significantly the inter-individual variability of hsCRP. The aim of this study was to identify genomic regions influencing hsCRP levels. A genome scan was performed in two independent studies of Caucasian populations, namely 513 Western-European families ascertained for myocardial infarction (n = 1,406) and 120 French-Canadian families diagnosed with hypertension (n = 758). In the myocardial infarction families, 31% of the inter-individual variation of hsCRP levels was explained by genetic factors (P = 0.0000015) and loci influencing hsCRP were identified on chromosomes 10 (at 141 cM) and 5 (at 150 cM) with multipoint LOD scores of 3.15 and 2.23, respectively. An additional suggestive signal was detected on chromosome 2 in subset analyses. A similar degree of heritability has been observed in a second independent population of French-Canadian hypertensive families for hsCRP (30%) and linkage results for chromosome 10 were confirmed with maximum LOD score of 2.7. We identified a chromosomal region in two independent populations which influences hsCRP in addition to several unique regions. This provides targets for the identification of genes involved in the regulation of hsCRP and the development and progression of vascular disease, including stroke.

Contrasting genetic structure in Plasmodium vivax populations from Asia and South America.

Populations of Plasmodium falciparum show striking differences in linkage disequilibrium, population differentiation and diversity, but only fragmentary data exists on the genetic structure of Plasmodium vivax. We genotyped nine tandem repeat loci bearing 2-8 bp motifs from 345 P. vivax infections collected from three Asian countries and from five locations in Colombia. We observed 9-37 alleles per locus and high diversity (He=0.72-0.79, mean=0.75) in all countries. Numbers of multiple clone infections varied considerably: these were rare in Colombia and India, but > 60% of isolates carried multiple alleles in at least one locus in Thailand and Laos. However, only one or two of the nine loci show >1 allele in many samples, suggesting that mutation within infections may result in overestimation of true multiple carriage rates. Identical nine-locus genotypes were frequently found in Colombian populations, contributing to strong linkage disequilibrium. These identical genotypes were strongly clustered in time, consistent with epidemic transmission of clones and subsequent breakdown of allelic associations, suggesting high rates of inbreeding and low effective recombination rates in this country. In contrast, identical genotypes were rare and loci were randomly associated in all three Asian populations, consistent with higher rates of outcrossing and recombination. We observed low but significant differentiation between different Asian countries (standardized FST = 0.13-0.45). In comparison, we see greater differentiation between collection locations within Colombia (standardized FST = 0.4-0.7), and strong differentiation between continents (standardized FST = 0.48-0.79). The observed heterogeneity in multiple clone carriage rates, linkage disequilibrium and population differentiation are similar in some, but not all, respects to those observed in P. falciparum, and have important implications for the design of association mapping studies, and interpretation of P. vivax epidemiology.

PET imaging in the photosensitive baboon: case-controlled study.

PURPOSE: The baboon (Papio hamadryas spp) offers a natural primate animal model of photosensitive generalized epilepsy. This study compared changes in cerebral blood flow (CBF) during intermittent light stimulation (ILS) between photosensitive and asymptomatic baboons. METHODS: Six photosensitive, epileptic (PS) and four nonphotosensitive, asymptomatic (CTL) baboons, matched for age, gender, and weight, were selected based on previous scalp EEG evaluation. Continuous intravenous ketamine (5-13 mg/kg) was used for sedation. Subjects underwent five sequential blood-flow PET studies within 60 min with 20 mCi (15)O-labeled water. Images were acquired in 3D mode (CTI/Siemens HR+ scanner, 63 contiguous slices, 2.4-mm thickness). Three resting scans were alternated with two activation scans during ILS. ILS was performed at 25 Hz for 60 s before to 60 s after the start of an activation scan. PET images were coregistered with MRI (3T Siemens Trio, T(1)-weighted 3D Turboflash sequence; TE/TR/TI, 3.04/2,100/785 ms; flip angle, 13 degrees). PET scans were reviewed and corrected for motion artifact. Resting scans were contrasted with activation scans and averaged independently for both groups. Quantitative CBF analyses were performed for the occipital and motor cortices. RESULTS: The CTL baboons showed greatest ILS-induced activation in the left middle frontal and inferior temporal gyri, left brainstem structures and right postcentral gyrus, bilateral occipital lobes, and in the posterior cingulate gyrus and cerebellum. In contrast, the PS animals showed strongest ILS activation in the right anterior cingulate and medial orbital gyri, amygdala, globus pallidum, and left inferior and superior temporal gyri. A striking finding was the absence of occipital and variable motor cortex activation in the PS animals. Deactivations were noted in the right orbitofrontal and anterior cingulate cortices in the CTL baboons and in the posterior cingulate gyrus, brainstem and cerebellum of the PS animals. CONCLUSIONS: The patterns of ILS-induced CBF changes differed between CTL and PS groups. These differences of activations and inhibitions suggest involvement of specific cortical-subcortical or networks in photosensitivity.