Genome-Wide Association Analysis of Neonatal White Matter Microstructure.

A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles. HFPRM revealed a latent measure of white matter microstructure that explained approximately 50% of variation in our tractography-based measures and accounted for a large proportion of heritable variation in each individual bundle. An intronic SNP in PSMF1 on chromosome 20 exceeded the conventional GWAS threshold of 5 x 10-8 (p = 4.61 x 10-8). Additional loci nearing genome-wide significance were located near genes with known roles in axon growth and guidance, fasciculation, and myelination.

Personalized connectome fingerprints: Their importance in cognition from childhood to adult years.

Structural neural network architecture patterns in the human brain could be related to individual differences in phenotype, behavior, genetic determinants, and clinical outcomes from neuropsychiatric disorders. Recent studies have indicated that a personalized neural (brain) fingerprint can be identified from structural brain connectomes. However, the accuracy, reproducibility and translational potential of personalized fingerprints in terms of cognition is not yet fully determined. In this study, we introduce a dynamic connectome modeling approach to identify a critical set of white matter subnetworks that can be used as a personalized fingerprint. Several individual variable assessments were performed that demonstrate the accuracy and practicality of personalized fingerprint, specifically predicting the identity and IQ of middle age adults, and the developmental quotient in toddlers. Our findings suggest the fingerprint found by our dynamic modeling approach is sufficient for differentiation between individuals, and is also capable of predicting general intellectual ability across human development.

Altered Brain Structure in Infants with Turner Syndrome.

Turner syndrome (TS) is a genetic disorder affecting approximately 1:2000 live-born females. It results from partial or complete X monosomy and is associated with a range of clinical issues including a unique cognitive profile and increased risk for certain behavioral problems. Structural neuroimaging studies in adolescents, adults, and older children with TS have revealed altered neuroanatomy but are unable to identify when in development differences arise. In addition, older children and adults have often been exposed to years of growth hormone and/or exogenous estrogen therapy with potential implications for neurodevelopment. The study presented here is the first to test whether brain structure is altered in infants with TS. Twenty-six infants with TS received high-resolution structural MRI scans of the brain at 1 year of age and were compared to 47 typically developing female and 39 typically developing male infants. Results indicate that the typical neuroanatomical profile seen in older individuals with TS, characterized by decreased gray matter volumes in premotor, somatosensory, and parietal-occipital cortex, is already present at 1 year of age, suggesting a stable phenotype with origins in the prenatal or early postnatal period.

FSEM: Functional Structural Equation Models for Twin Functional Data.

The aim of this paper is to develop a novel class of functional structural equation models (FSEMs) for dissecting functional genetic and environmental effects on twin functional data, while characterizing the varying association between functional data and covariates of interest. We propose a three-stage estimation procedure to estimate varying coefficient functions for various covariates (e.g., gender) as well as three covariance operators for the genetic and environmental effects. We develop an inference procedure based on weighted likelihood ratio statistics to test the genetic/environmental effect at either a fixed location or a compact region. We also systematically carry out the theoretical analysis of the estimated varying functions, the weighted likelihood ratio statistics, and the estimated covariance operators. We conduct extensive Monte Carlo simulations to examine the finite-sample performance of the estimation and inference procedures. We apply the proposed FSEM to quantify the degree of genetic and environmental effects on twin white-matter tracts obtained from the UNC early brain development study.

Genome-wide association analysis identifies common variants influencing infant brain volumes.

Genome-wide association studies (GWAS) of adolescents and adults are transforming our understanding of how genetic variants impact brain structure and psychiatric risk, but cannot address the reality that psychiatric disorders are unfolding developmental processes with origins in fetal life. To investigate how genetic variation impacts prenatal brain development, we conducted a GWAS of global brain tissue volumes in 561 infants. An intronic single-nucleotide polymorphism (SNP) in IGFBP7 (rs114518130) achieved genome-wide significance for gray matter volume (P=4.15 × 10-10). An intronic SNP in WWOX (rs10514437) neared genome-wide significance for white matter volume (P=1.56 × 10-8). Additional loci with small P-values included psychiatric GWAS associations and transcription factors expressed in developing brain. Genetic predisposition scores for schizophrenia and ASD, and the number of genes impacted by rare copy number variants (CNV burden) did not predict global brain tissue volumes. Integration of these results with large-scale neuroimaging GWAS in adolescents (PNC) and adults (ENIGMA2) suggests minimal overlap between common variants impacting brain volumes at different ages. Ultimately, by identifying genes contributing to adverse developmental phenotypes, it may be possible to adjust adverse trajectories, preventing or ameliorating psychiatric and developmental disorders.

Newborn insula gray matter volume is prospectively associated with early life adiposity gain.

BACKGROUND: The importance of energy homeostasis brain circuitry in the context of obesity is well established, however, the developmental ontogeny of this circuitry in humans is currently unknown. Here, we investigate the prospective association between newborn gray matter (GM) volume in the insula, a key brain region underlying energy homeostasis, and change in percent body fat accrual over the first six months of postnatal life, an outcome that represents among the most reliable infant predictors of childhood obesity risk. METHODS: A total of 52 infants (29 male, 23 female, gestational age at birth=39(1.5) weeks) were assessed using structural MRI shortly after birth (postnatal age at MRI scan=25.9(12.2) days), and serial Dual X-Ray Absorptiometry shortly after birth (postnatal age at DXA scan 1=24.6(11.4) days) and at six months of age (postnatal age at DXA scan 2=26.7(3.3) weeks). RESULTS: Insula GM volume was inversely associated with change in percent body fat from birth to six-months postnatal age and accounted for 19% of its variance (ß=-3.6%/S.D., P=0.001). This association was driven by the central-posterior portion of the insula, a region of particular importance for gustation and interoception. The direction of this effect is in concordance with observations in adults, and the results remained statistically significant after adjusting for relevant covariates and potential confounding variables. CONCLUSIONS: Altogether, these findings suggest an underlying neural basis of childhood obesity that precedes the influence of the postnatal environment. The identification of plausible brain-related biomarkers of childhood obesity risk that predate the influence of the postnatal obesogenic environment may contribute to an improved understanding of propensity for obesity, early identification of at-risk individuals, and intervention targets for primary prevention.

Exploratory study of once-daily transcranial direct current stimulation (tDCS) as a treatment for auditory hallucinations in schizophrenia.

BACKGROUND: Auditory hallucinations are resistant to pharmacotherapy in about 25% of adults with schizophrenia. Treatment with noninvasive brain stimulation would provide a welcomed additional tool for the clinical management of auditory hallucinations. A recent study found a significant reduction in auditory hallucinations in people with schizophrenia after five days of twice-daily transcranial direct current stimulation (tDCS) that simultaneously targeted left dorsolateral prefrontal cortex and left temporo-parietal cortex. HYPOTHESIS: We hypothesized that once-daily tDCS with stimulation electrodes over left frontal and temporo-parietal areas reduces auditory hallucinations in patients with schizophrenia. METHODS: We performed a randomized, double-blind, sham-controlled study that evaluated five days of daily tDCS of the same cortical targets in 26 outpatients with schizophrenia and schizoaffective disorder with auditory hallucinations. RESULTS: We found a significant reduction in auditory hallucinations measured by the Auditory Hallucination Rating Scale (F2,50=12.22, P<0.0001) that was not specific to the treatment group (F2,48=0.43, P=0.65). No significant change of overall schizophrenia symptom severity measured by the Positive and Negative Syndrome Scale was observed. CONCLUSIONS: The lack of efficacy of tDCS for treatment of auditory hallucinations and the pronounced response in the sham-treated group in this study contrasts with the previous finding and demonstrates the need for further optimization and evaluation of noninvasive brain stimulation strategies. In particular, higher cumulative doses and higher treatment frequencies of tDCS together with strategies to reduce placebo responses should be investigated. Additionally, consideration of more targeted stimulation to engage specific deficits in temporal organization of brain activity in patients with auditory hallucinations may be warranted.

Diffusion tensor imaging detects abnormalities in the corticospinal tracts of neonates with infantile Krabbe disease.

BACKGROUND AND PURPOSE: It is not possible to determine if neonates diagnosed with Krabbe disease through statewide neonate screening programs will develop the disease as infants, juveniles, or adults. The only available treatment for this fatal neurodegenerative condition is unrelated umbilical cord transplantation, but this treatment is only effective before clinical symptoms appear. Therefore, a marker of disease progression is needed. The purpose of this study was to evaluate the use of diffusion tensor imaging (DTI) with fiber tracking in identifying early changes in major motor tracts of asymptomatic neonates with infantile Krabbe disease. MATERIALS AND METHODS: Six neonates with infantile Krabbe disease identified because of family history underwent brain MR imaging within the first 4 weeks of life. Six-direction DTI and quantitative tractography of the corticospinal tracts were performed. Hypothesis tests, 1 for each hemisphere, were used to determine whether the fractional anisotropy (FA) ratio of the neonates with infantile Krabbe disease was significantly different from that of 45 age- and sex-matched controls. RESULTS: The average FA ratio for patients with Krabbe disease was 0.89 and 0.87 for left and right tracts, respectively (P = .002 and < .001). After adjusting for gestational age, gestational age at birth, birth weight, sex, and race, the 6 patients with Krabbe disease had significantly lower FA values than the controls (P < .001). CONCLUSIONS: DTI with quantitative tractography detected significant differences in the corticospinal tracts of asymptomatic neonates who had the early-onset form of Krabbe disease. Once standardized and validated, this tool has the potential to be used as a marker of disease progression in neonates diagnosed through statewide neonate screening programs.

Developmental regulation of neural cell adhesion molecule in human prefrontal cortex.

Neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule that exerts important functions in normal neurodevelopment including cell migration, neurite outgrowth, axon fasciculation, and synaptic plasticity. Alternative splicing of NCAM mRNA generates three main protein isoforms: NCAM-180, -140, and -120. Ectodomain shedding of NCAM isoforms can produce an extracellular 105-115 kilodalton soluble neural cell adhesion molecule fragment (NCAM-EC) and a smaller intracellular cytoplasmic fragment (NCAM-IC). NCAM also undergoes a unique post-translational modification in brain by the addition of polysialic acid (PSA)-NCAM. Interestingly, both PSA-NCAM and NCAM-EC have been implicated in the pathophysiology of schizophrenia. The developmental expression patterns of the main NCAM isoforms and PSA-NCAM have been described in rodent brain, but no studies have examined NCAM expression across human cortical development. Western blotting was used to quantify NCAM in human postmortem prefrontal cortex in 42 individuals ranging in age from mid-gestation to early adulthood. Each NCAM isoform (NCAM-180, -140, and -120), post-translational modification (PSA-NCAM) and cleavage fragment (NCAM-EC and NCAM-IC) demonstrated developmental regulation in frontal cortex. NCAM-180, -140, and -120, as well as PSA-NCAM, and NCAM-IC all showed strong developmental regulation during fetal and early postnatal ages, consistent with their identified roles in axon growth and plasticity. NCAM-EC demonstrated a more gradual increase from the early postnatal period to reach a plateau by early adolescence, potentially implicating involvement in later developmental processes. In summary, this study implicates the major NCAM isoforms, PSA-NCAM and proteolytically cleaved NCAM in pre- and postnatal development of the human prefrontal cortex. These data provide new insights on human cortical development and also provide a basis for how altered NCAM signaling during specific developmental intervals could affect synaptic connectivity and circuit formation, and thereby contribute to neurodevelopmental disorders.

Temporal and spatial development of axonal maturation and myelination of white matter in the developing brain.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) has been widely used to investigate the development of white matter (WM). However, information about this development in healthy children younger than 2 years of age is lacking, and most previous studies have only measured fractional anisotropy (FA). This study used FA and radial and axonal diffusivities in children younger than 2 years of age, aiming to determine the temporal and spatial development of axonal maturation and myelination of WM in healthy children. MATERIALS AND METHODS: A total of 60 healthy pediatric subjects were imaged by using a 3T MR imaging scanner. They were divided into 3 groups: 20 at 3 weeks, 20 at 1 year of age, and 20 at 2 years of age. All subjects were imaged asleep without sedation. FA and axial and radial diffusivities were obtained. Eight regions of interest were defined, including both central and peripheral WM for measuring diffusion parameters. RESULTS: A significant elevation in FA (P < .0001) and a reduction in axial and radial diffusivities (P < .0001) were observed from 22 days to 1 year of age, whereas only radial diffusivity showed significant changes (P = .0014) from 1 to 2 years of age. The region-of-interest analysis revealed that FA alone may not depict the underlying biologic underpinnings of WM development, whereas directional diffusivities provide more insights into the development of WM. Finally, the spatial development of WM begins from the central to the peripheral WM and from the occipital to the frontal lobes. CONCLUSIONS: With both FA and directional diffusivities, our results demonstrate the temporal and spatial development of WM in healthy children younger than 2 years of age.

Functional connectivity MR imaging reveals cortical functional connectivity in the developing brain.

BACKGROUND AND PURPOSE: Unlike conventional functional MR imaging where external sensory/cognitive paradigms are needed to specifically activate different regions of the brain, resting functional connectivity MR imaging acquires images in the absence of cognitive demands (a resting condition) and detects brain regions, which are highly temporally correlated. Therefore, resting functional MR imaging is highly suited for the study of brain functional development in pediatric subjects. This study aimed to determine the temporal and spatial patterns of rfc in healthy pediatric subjects between 2 weeks and 2 years of age. MATERIALS AND METHODS: Rfc studies were performed on 85 children: 38 neonates (2-4 weeks of age), 26 one-year-olds, and 21 two-year-olds. All subjects were imaged while asleep; no sedation was used. Six regions of interest were chosen, including the primary motor, sensory, and visual cortices in each hemisphere. Mean signal intensity of each region of interest was used to perform correlation analysis pixel by pixel throughout the entire brain, identifying regions with high temporal correlation. RESULTS: Functional connectivity was observed in all subjects in the sensorimotor and visual areas. The percent brain volume exhibiting rfc and the strength of rfc continued to increase from 2 weeks to 2 years. The growth trajectories of the percent brain volume of rfc appeared to differ between the sensorimotor and visual areas, whereas the z-score was similar. The percent brain volume of rfc in the sensorimotor area was significantly larger than that in the visual area for subjects 2 weeks of age (P = .008) and 1-year-olds (P = .017) but not for the 2-year-olds. CONCLUSIONS: These findings suggest that rfc in the sensorimotor precedes that in the visual area from 2 weeks to 1 year but becomes comparable at 2 years. In contrast, the comparable z-score values between the sensorimotor and visual areas for all age groups suggest a disassociation between percent brain volume and the strength of cortical rfc.

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood.

Previous studies of postnatal synaptic development in human frontal cortex have shown that synaptic density rises after birth, reaches a plateau in childhood and then decreases to adult levels by late adolescence. A similar pattern has been seen in nonhuman primate cortex. These earlier studies in human cortex are limited, however, by significant age gaps in study subjects at critical inflection points of the developmental curve. Additionally, it is unclear if synaptic development occurs in different patterns in different cortical layers in prefrontal cortex (PFC). The purpose of this study was to examine synaptic density in human PFC across development by measuring two synaptic marker proteins: synaptophysin (presynaptic), and postsynaptic density protein 95 (PSD-95; postsynaptic). Western blotting was used to assess the relative levels of synaptophysin and PSD-95 in dorsolateral PFC of 42 subjects, distributed in age from 18 weeks gestation to 25 years. In addition, synaptophysin immunoreactivity was examined in each layer of areas 9 and 46 of PFC in 24 subjects, ranging in age from 0.1-25 years. Synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10. Synaptophysin subsequently decreased until the adult level was reached by mid-adolescence, around age 16. PSD-95 levels increased postnatally to reach a stable plateau by early childhood with a slight reduction in late adolescence and early adulthood. The pattern of synaptophysin immunoreactivity seen with immunohistochemistry was similar to the Western experiments but the changes across age were more subtle, with little change by layer within and across age. The developmental patterns exhibited by these synaptic marker proteins expand upon previous studies of developmental synaptic changes in human frontal cortex; synaptic density increases steadily from birth to late childhood, then decreases in early adolescence to reach adult levels by late adolescence.

Early postnatal development of corpus callosum and corticospinal white matter assessed with quantitative tractography.

BACKGROUND AND PURPOSE: The early postnatal period is perhaps the most dynamic phase of white matter development. We hypothesized that the early postnatal development of the corpus callosum and corticospinal tracts could be studied in unsedated healthy neonates by using novel approaches to diffusion tensor imaging (DTI) and quantitative tractography. MATERIALS AND METHODS: Isotropic 2 x 2 x 2 mm(3) DTI and structural images were acquired from 47 healthy neonates. DTI and structural images were coregistered and fractional anisotropy (FA), mean diffusivity (MD), and normalized T1-weighted (T1W) and T2-weighted (T2W) signal intensities were determined in central midline and peripheral cortical regions of the white matter tracts of the genu and splenium of the corpus callosum and the central midbrain and peripheral cortical regions of the corticospinal tracts by using quantitative tractography. RESULTS: We observed that central regions exhibited lower MD, higher FA values, higher T1W intensity, and lower T2W intensity than peripheral cortical regions. As expected, MD decreased, FA increased, and T2W signal intensity decreased with increasing age in the genu and corticospinal tract, whereas there was no significant change in T1W signal intensity. The central midline region of the splenium fiber tract has a unique pattern, with no change in MD, FA, or T2W signal intensity with age, suggesting different growth trajectory compared with the other tracts. FA seems to be more dependent on tract organization, whereas MD seems to be more sensitive to myelination. CONCLUSIONS: Our novel approach may detect small regional differences and age-related changes in the corpus callosum and corticospinal white matter tracts in unsedated healthy neonates and may be used for future studies of pediatric brain disorders that affect developing white matter.

Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia.

BACKGROUND: Cytokines demonstrate diverse actions in the brain and modulate systemic and central nervous system (CNS) responses to injury, infection, and inflammation. Cytokines in the CNS are elevated during infection and ischemia, two neurodevelopmental insults associated with increased schizophrenia risk. We hypothesize that cytokine-mediated neuronal injury during development may contribute to schizophrenia pathophysiology, causing subtle alterations in neuronal number and density. METHODS: We examined cytokine regulation of neuronal number in embryonic day 18 rat cortical cultures using MAP-2 immunohistochemistry. Mixed cultures derived from frontal cortex were fixed and stained after 48-hour exposure to the proinflammatory interleukin-1beta (IL-1beta), interleukin-6 (IL-6), or tumor necrosis factor-alpha (TNF-alpha; 0, 10, 100, or 1000 units/mL). RESULTS: IL-1beta (maximum effect 35%) and IL-6 (maximum effect 29%) produced dose-dependent decreases in the number of cells (neurons) immunoreactive for MAP-2 antibody, suggesting decreased neuronal survival. TNF-alpha also tended to decrease MAP-2 immunostaining at the highest dose tested. CONCLUSIONS: Our data suggest a role for cytokines in the modulation of neuronal survival during neurodevelopment, a finding potentially relevant to schizophrenia pathophysiology. If cytokine-mediated neuronal injury proves to be a common response to gestational insults associated with increased schizophrenia risk, the pharmacologic modulation of these molecules may have clinical utility.

Welcome to the experience economy. It's no longer just about healing: patients want a personal transformation.

Health care is no longer just about healing: patients want a "personal transformation," a way to be made whole again. How can your organization think about making the play from services to experiences to transformations, but without your organization's dropping the ball?

Infant cerebral ventricle volume: a comparison of 3-D ultrasound and magnetic resonance imaging.

Enlargement of the cerebral lateral ventricles is observed in several neuropsychiatric disorders with origins in early brain development. Lateral ventricle size is also predictive of poor neurodevelopmental outcome in premature infants. Three-dimensional (3-D) ultrasound (US) offers an improved methodology for the study of lateral ventricle volume in neonates and infants. To assess the validity of ventricle volume measures obtained with 3-D US, we compared the volumes obtained by 3-D US with magnetic resonance imaging (MRI) in seven infants. Ventricle volumes were determined using a computer-assisted image analysis program, IRIS. There was excellent correlation between ventricle volumes obtained with 3-D US and those obtained with MRI (intraclass correlation coefficient 0.92, F = 23.28, p = 0.00027), indicating that 3-D US provides valid measures of overall lateral ventricle volume compared to the "gold standard" of MRI. 3-D US can provide an economical and practical means of studying lateral ventricle volume in neonates, a neurostructural marker of abnormal brain development.

Outcome in children with fetal mild ventriculomegaly: a case series.

Mild enlargement of the lateral ventricles is associated with schizophrenia and other neurodevelopmental disorders. While it has been hypothesized that ventricle abnormalities associated with neurodevelopmental disorders arise during fetal brain development, there is little direct evidence to support this hypothesis. Using ultrasound, it is possible to image the fetal ventricles in utero. Fetal mild ventriculomegaly (MVM) has been associated with developmental delays in early childhood, though longer-term neurodevelopmental outcome has not been studied. Follow-up of five children (aged 4--9 years) with mild enlargement of the lateral ventricles on prenatal ultrasound and two unaffected co-twins is reported: one child had attention deficit hyperactivity disorder (ADHD), one had autism, and two had evidence of learning disorders. These cases suggest that the mild enlargement of the lateral ventricles associated with these neurodevelopmental disorders arises during fetal brain development and can be detected with prenatal ultrasound. In addition, the presence of mildly enlarged, asymmetric ventricles in two children on prenatal ultrasound and on follow-up MRI at age 6 years indicates that ventricle structure present in utero can persist well into childhood brain development. The study of fetal ventricle development with ultrasound may provide important insights into neurodevelopmental disorders and allow the identification of children at high risk.

Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain.

Prenatal exposure to infection appears to increase the risk of schizophrenia and other neurodevelopmental disorders. We have hypothesized that cytokines, generated in response to maternal infection, play a key mechanistic role in this association. E16 timed pregnancy rats were injected i.p. with Escherichia coli lipopolysaccharide (LPS) to model prenatal exposure to infection. Placenta, amniotic fluid and fetal brains were collected 2 and 8h after LPS exposure. There was a significant treatment effect of low-dose (0.5mg/kg) LPS on placenta cytokine levels, with significant increases of interleukin (IL)-1beta (P<0.0001), IL-6 (P<0.0001), and tumor necrosis factor-alpha (TNF-alpha) (P=0.0001) over the 2 and 8h time course. In amniotic fluid, there was a significant effect of treatment on IL-6 levels (P=0.0006). Two hours after maternal administration of high-dose (2.5mg/kg) LPS, there were significant elevations of placenta IL-6 (P<0.0001), TNF-alpha (P<0.0001), a significant increase of TNF-alpha in amniotic fluid (P=0.008), and a small but significant decrease in TNF-alpha (P=0.035) in fetal brain. Maternal exposure to infection alters pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain.

Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia.

BACKGROUND: The etiology of schizophrenia remains unknown; however, a role for apoptosis has been hypothesized. Bcl-2 is a potent inhibitor of apoptosis and also exerts neurotrophic activity in the central nervous system (CNS). Bcl-2 expression is increased in the CNS of several neurodegenerative disorders. Given that schizophrenia has certain features of a limited neurodegenerative disorder, it was hypothesized that cortical Bcl-2 expression is increased in schizophrenia. METHODS: Postmortem temporal cortex was obtained from the Stanley Foundation Neuropathology Consortium with matched control, schizophrenic, bipolar, and depressed subjects. Bcl-2 protein was measured by enzyme-linked immunoassay (ELISA) and Western blot. Primary analysis was limited to schizophrenia versus control subjects. RESULTS: The ELISA demonstrated 25% less Bcl-2 protein in schizophrenia (p =.046), supported by Western blot results. A secondary analysis of schizophrenic and bipolar subjects revealed twofold higher mean Bcl-2 in antipsychotic-treated versus neuroleptic-naive subjects. CONCLUSIONS: Contrary to our hypothesis, cortical Bcl-2 was reduced in schizophrenia. This supports the notion that schizophrenia is not a classic neurodegenerative disorder; however, less Bcl-2 protein may signal neuronal vulnerability to proapoptotic stimuli and to neuronal atrophy. Also, the association between neuroleptic exposure and higher Bcl-2 levels could underlie the favorable long-term outcomes of patients who receive maintenance antipsychotic treatment.