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PubMedDate not supplied

Research in psychopathology: epistemologic issues.

Etiologic research in psychiatry relies on an objectivist epistemology positing that human cognition is specified by the "reality" of the outer world, which consists of a totality of mind-independent objects. Truth is considered as some sort of correspondence relation between words and external objects, and mind as a mirror of nature. In our view, this epistemology considerably impedes etiologic research. Objectivist epistemology has been recently confronting a growing critique from diverse scientific fields. Alternative models in neurosciences (neuronal selection), artificial intelligence (connectionism), and developmental psychology (developmental biodynamics) converge in viewing living organisms as self-organizing systems. In this perspective, the organism is not specified by the outer world, but enacts its environment by selecting relevant domains of significance that constitute its world. The distinction between mind and body or organism and environment is a matter of observational perspective. These models from empirical sciences are compatible with fundamental tenets of philosophical phenomenology and hermeneutics. They imply consequences for research in psychopathology: symptoms cannot be viewed as disconnected manifestations of discrete localized brain dysfunctions. Psychopathology should therefore focus on how the person's self-coherence is maintained and on the understanding and empirical investigation of the systemic laws that govern neurodevelopment and the organization of human cognition.

Humans↗

PubMedDate not supplied

Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited.

Several lines of evidence support the notion that a substantial reorganization of cortical connections, involving a programmed synaptic pruning, takes place during adolescence in humans. A review of neurobiological abnormalities in schizophrenia indicates that the neurobiological parameters that undergo peripubertal regressive changes may be abnormal in this disorder. An excessive pruning of the prefrontal corticocortical, and corticosubcortical synapses, perhaps involving the excitatory glutamatergic inputs to pyramidal neurons, may underlie schizophrenia. A reciprocal failure of pruning in certain subcortical structures, such as lenticular nuclei, may also occur. Several developmental trajectories, related to early brain insults as well as genetic factors affecting postnatal neurodevelopment, could lead to the illness. These models would have heuristic value and may be consistent with several known facts of the schizophrenic illness, such as its onset in adolescence and the gender differences in its onset and natural course. The relationship between these models and other etiological models of schizophrenia are summarized and approaches to test relevant hypotheses are discussed.

Age of Onset↗

PubMed1991

Factor analysis and the cerebral hemispheres: pilot study and parietal functions.

Although research on lateral differences has proliferated, attempts to specify fundamental dichotomies of hemispheric processing have yielded less than satisfactory results. The factor analysis of behavioral asymmetries can provide a different approach by helping to identify common functions underlying disparate tasks. It can also provide information on individual differences and interrelationships among functions. Here, the viability of the approach is demonstrated with a small pilot study (N = 29), and with two larger experiments (N = 70 and N = 60) that stress parietal lobe function. Seven lateralized functions were identified: auditory lexical, spatial attentive, spatial positional, spatial quantitative, tactile figural, visual emotional and visual lexical. A range of positive, negative and null correlations was found between functions, contrary to lateralization strength, hemisphericity, and independence models of individual differences in lateralization. However, a pattern of intercorrelations was observed among functions believed to be localized to the perisylvian region (Brodmann areas 22 and 39), which is consistent with the neurodevelopment theory of Geschwind and Galaburda (Cerebral Lateralization Biological Mechanisms, Associations and Pathology, The MIT Press, Cambridge, MA, 1987).

Adult↗

PubMed1996

Short-term memory in children with Williams syndrome: a reduced contribution of lexical--semantic knowledge to word span.

Williams syndrome (WS) is a genetic syndrome of abnormal neurodevelopment, characterised by a specific linguistic pattern. Comparing performances of WS subjects with those of normal children in a word span task, we found that WS subjects revealed normal phonological similarity and length effects but a reduced frequency effect. Our results suggest comparable phonological encoding mechanisms in WS and normal controls and, at the same time, it provides evidence for an impaired access to lexical-semantic knowledge in WS subjects. This dissociation fits well with the particular pattern of linguistic abilities of these subjects.

Child↗

PubMed1996

Predicting haloperidol treatment response in chronic schizophrenia.

The study attempted to identify pretreatment characteristics of chronic schizophrenic patients that would predict remission in psychosis and amount of clinical improvement after treatment with haloperidol. Thirty-five acutely relapsed schizophrenic patients were entered into a blind 6-week treatment protocol. Pretreatment measures were assessed for prediction of both remission status (dichotomous) and for correlations with change in psychopathology (continuous). Later age of onset and higher plasma homovanillic acid values were significant predictors of remission status (model 1). However, higher cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol, as well as indices of normal neurodevelopment, predicted larger changes in psychopathology. The results indicate that the definition of drug response determines the predictive variables. Dopaminergic activity seems to relate to the ability to reach remission, while noradrenergic activity relates to symptom intensity and reduction. In addition to catecholamine activity, neurodevelopmental changes determine response to haloperidol.

Adult↗

PubMed1990

5-HT1A receptors control neurite branching during development.

Serotonin (5-HT) is known to affect the motility and structure of responsive growth cones and to influence synaptic density in vitro. Whether these effects are produced via membrane bound serotonin receptors or another mechanism has been unknown. We demonstrate that high-affinity 5-HT receptors, present prenatally in rat brain, are asymmetrically distributed among cultured cortical neurons. Stimulation of the 5-HT1A receptors of these neurons in vitro specifically decreases the branching of neurites by 70% and reduces total neuritic length by more than half. These results are compatible with subtypes of serotonin receptors having important roles in mammalian neurodevelopment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Rate of recovery of D1 and D2 dopaminergic receptors in young vs. adult rat striatal tissue following alkylation with ethoxycarbonyl-ethoxy-dihydroquinoline (EEDQ).

The rate of recovery of D1 and D2 receptor binding sites in rat striatal tissue labeled with [3H]SCH-23390 or [3H]YM-09151-2 was followed daily after irreversible blockade of these receptors with the alkylating agent ethoxycarbonyl-ethoxy-dihydroquinoline (EEDQ). These rates were significantly higher in young post-weaning rats than in young adults (14% vs. 7% per day). The findings suggest that rates of synthesis of new D1 and D2 receptor proteins may be increased during a phase of neurodevelopment in the first postnatal month when the accumulation of both receptor types, especially of D1 receptors, is about maximal.

Alkylating Agents↗

PubMed1995

Developmental changes in the inducibility of fos-like immunoreactivity in primary embryonic spinal cord cultures.

The immediate early gene (IEG) transcription factor c-fos coordinates changes in the pattern of long term gene expression and, therefore, it may be involved in mediating epigenetic control during neurodevelopment. We used pharmacological treatments mimicking various environmental and intracellular signals and assessed the inducibility of fos-like immunoreactivity (LIR) at various stages of neurodifferentiation in a primary embryonic spinal cord culture system by immunohistochemistry. Constitutive fos LIR exclusively found in neurons, was driven by the onset and extent of spontaneous electrical activity, as it was blockable by tetrodotoxin (TTX) at all developmental stages. Phorbol myristate 13 acetate (PMA) increased the number of fos-LIR cells equally effectively at all stages, but the predominant cellular localization of fos-LIR changed through ontogeny. The effect of veratridine, kainate and serum-derived factors in significantly inducing fos-LIR was restricted to the earliest developmental stage (4 days in vitro; DIV) investigated; whereas forskolin, the GABAA antagonist picrotoxin and NMDA failed to induce fos-LIR at this stage, but increased the number of fos-LIR neurons at later stages. Dihydropyridine agonists of the voltage-sensitive calcium channels (VSCC) raised the number of fos-LIR neurons and also prevented TTX-mediated down-regulation; whereas antagonists markedly reduced fos-LIR at all ages. Either type of NMDA antagonists (AP5 and MK801) and the GABAA agonist muscimol significantly reduced fos-LIR at all ages. These findings demonstrate that the inducibility of fos-LIR is substantially different in embryonic neurons than in adult ones and that inducibility by various first and second messengers is dependent on the development stage.

Animals↗

PubMed1994

Temporal lobe sulco-gyral pattern anomalies in schizophrenia: an in vivo MR three-dimensional surface rendering study.

Neuroanatomical and histological findings from post-mortem brains, as well as in vivo findings from magnetic resonance imaging (MRI) studies, suggest the presence of morphologic temporal lobe abnormalities in schizophrenia. To determine whether or not sulco-gyral pattern abnormalities in the temporal lobe could be detected in vivo, we applied computerized surface rendering techniques to MR data sets in order to make both qualitative and quantitative analyses of three-dimensional reconstructions of the temporal and frontal cortex in 15 schizophrenic patients and 15 normal controls. The qualitative analysis, based on a visual classification of the temporal lobe sulco-gyral pattern by 4 raters blind to diagnosis, showed that in schizophrenics there was a more vertical orientation to the sulci in the left temporal lobe, with an interrupted course of sulci due to gyri coursing across the sulci. Normal controls, in contrast, showed a more horizontal orientation with no interruptions. These findings were supported by the quantitative analysis, where more sulcal lines, representing an interrupted course of sulci, were observed in the temporal lobes (more pronounced on the left) in schizophrenics than in normal controls. These data suggest that some of the abnormalities observed in schizophrenia may have their origin in alterations occurring during the course of neurodevelopment when the sulco-gyral pattern is determined.

Adult↗

PubMed1994

Different omega-conotoxins mark the development of Swiss Webster mouse cortex suggesting N-type voltage sensitive calcium channel subtypes.

omega-GVIA conotoxin has been used to mark presynaptic N-type voltage sensitive calcium channels (VSCC). Litzinger et al. used omega-conotoxin binding to describe a critical period of neurodevelopment in Swiss Webster mice between postnatal days (PND) 11 and 14, which appears to be important to the initiation of proper final development of the central nervous system. In this study, we compare how three different omega-conotoxins (i.e. GVIA from Conus geographus, MVIIA from Conus magus, and RVIA from Conus radiatus) mark N-type VSCC during this critical period in Swiss Webster mouse cortex. 125I-GVIA was bound to Swiss Webster mouse cortex synaptosomal membrane fractions at postnatal days 8 and 14. 125I-GVIA binding displacement curves were obtained by incubating membranes with increasing concentrations of unlabeled GVIA, MVIIA, and RVIA. Displacement curves and IC50 were calculated for each of these three omega-conotoxins, and then compared. At PND 14, GVIA, MVIIA and RVIA were able to displace greater than 95% of 125I-GVIA binding. At PND 8, however, MVIIA was only able to displace 83% of 125I-GVIA binding, and RVIA was only able to block 84%. The IC50 does not appear to change significantly during this period of development for any of the omega-conotoxins. The inability of MVIIA and RVIA to completely block 125I-GVIA binding in pre-critical period Swiss Webster cortex denotes an alteration in the composition of N-type VSCC binding sites. With this data, we have suggested the presence of subtypes of the N-type VSCC in the cortex of pre-critical period Swiss Webster mouse.

Animals↗

PubMed1994

Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death.

In vitro studies have suggested that the NMDA receptor consists of an essential subunit, NR1, and various modulatory NR2 subunits. To test this hypothesis directly in vivo, we generated mice carrying a disrupted NR1 allele. NMDA-inducible increases in intracellular calcium and membrane currents were abolished in neurons from homozygous null mutants (NR1-/-). Thus, NR1 has a unique role, which cannot be substituted by any other subunit, in determining the activity of the endogenous NMDA receptor. A concomitant reduction in levels of NR2B but not NR2A occurred in NR1-/- mice, demonstrating that there is an interdependence of subunit expression. NR1-/- mice died 8-15 hr after birth, indicating a vital neonatal function for the NMDA receptor. Although the NMDA receptor has been implicated in several aspects of neurodevelopment, overall neuroanatomy of NR1-/- mice appeared normal. Pathological evidence suggested that respiratory failure was the ultimate cause of death.

Animals↗

PubMed1992

Loss of sylvian fissure asymmetry in schizophrenia. A quantitative post mortem study.

The sylvian fissure is known to be one of the most asymmetric structures of the human brain. Sylvian fissure length was measured in post-mortem brains of 35 schizophrenic patients and 33 matched non psychiatric control subjects. The schizophrenics showed a significantly reduced length of the left sylvian fissure (-16%, p less than 0.0001) compared to the control subjects, while the right sylvian fissure length was unchanged. Sylvian fissure asymmetry (left/right ratio) was more reduced in male schizophrenics (-24%, p less than 0.001) than in female patients (-16%, p less than 0.03). This finding is consistent with several post-mortem and MRI studies showing left temporal lobe pathology in a significant proportion of patients and may indicate that schizophrenia is a disorder of early neurodevelopment causing impaired cerebral lateralization.

Adult↗

PubMed1994

Membrane phospholipid metabolism and schizophrenia: an in vivo 31P-MR spectroscopy study.

Membrane phospholipid metabolism was studied with 31P magnetic resonance spectroscopy in the left dorsal prefrontal cortex of 19 male, medicated, schizophrenic patients and compared to 18 normal male controls matched in age, education and parental education level. The schizophrenic patients had significantly decreased phosphomonoester levels (PMEs, metabolites predominantly involved in the synthesis of membrane phospholipids). Phosphodiester levels (PDEs, breakdown products of membrane phospholipids) were not statistically different in schizophrenic patients compared to controls. However, a significant increase in the PDE levels was observed in the newly diagnosed patient subgroup. This observed pattern of the PMEs and PDEs would be consistent with the presence of an abnormal neurodevelopment early in the illness of schizophrenia.

Adolescent↗

PubMed1991

The brain stem reticular formation in schizophrenia.

Post-mortem brain tissue was obtained from four patients with schizophrenia and five controls to study cell groups in the brain stem reticular formation. Cholinergic neurons in the pedunculopontine nucleus (PPN) and lateral dorsal tegmental nucleus (LDT) were labeled using nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase histochemistry, while catecholaminergic neurons of the locus ceruleus (LC) were labeled immunocytochemically using an antibody to tyrosine hydroxylase. In schizophrenic patients, there were increased numbers of neurons in the PPN labeled by NADPH-diaphorase and reduced cell size in the LC. These results implicate the reticular formation as a possible pathophysiological site for at least some patients with schizophrenia. This also suggests that some of the deficits observed may be based on faulty neurodevelopment.

Aged↗

PubMed1996

Semaphorins: mediators of repulsive growth cone guidance.

During development, neuronal growth cones encounter a variety of guidance cues while mediating axon path finding, target recognition and synapse formation. It is clear that repulsive guidance mechanisms play an essential role in these processes. The semaphorin gene family, which is conserved from invertebrates to mammals, includes members that mediate repulsive guidance. Molecular and cellular analysis of this gene family is providing insight into how inhibitory cues function during neurodevelopment.

Journal Article↗

PubMed2005

Characterization of brain plasticity in schizophrenia using template deformation.

RATIONALE AND OBJECTIVE: Abnormal neurodevelopment may play a role in the pathophysiology of schizophrenia. We used deformation-based morphometry to examine voxel-wise age-related changes in patients with schizophrenia compared with healthy brains. MATERIALS AND METHODS: We used a set of skull-stripped brains from an image database of cranial magnetic resonance images. We then deformed a template brain to the rest of the brains creating a set of deformation fields. Using the Jacobian values of these deformation fields, we calculated the voxel-wise t-score for comparison of controls with patients. We also calculated the voxel-wise Pearson correlation of Jacobian with age for both controls and patients. RESULTS: By examining the volume renderings of these statistical fields, we found that healthy people undergo age-related expansion of the ventricles, the surrounding periventricular white matter, and a corresponding decline in the frontal lobes and cingulate gyrus. In contrast, patients show much less of this age-related expansion of the ventricles and less atrophy in the cerebral cortex. In addition, patients have larger ventricles and reduced volume in the frontal/parietal lobes. CONCLUSION: These constellations of findings suggest that otherwise normal age-related ventricular enlargement and cortical loss occurs in schizophrenia patients, albeit at an earlier age.

Adolescent↗

PubMed2005

Regional structural characterization of the brain of schizophrenia patients.

RATIONALE AND OBJECTIVES: We study morphologic characteristics and age-related changes in patients with schizophrenia to investigate whether abnormal neurodevelopment and brain structure have a role in the pathophysiological course of this disease. MATERIALS AND METHODS: Our data consist of a set of cranial magnetic resonance images of 46 patients with schizophrenia and age- and sex-matched healthy controls. We deformed a template brain image to our set of subject images. Jacobian fields of these deformations were reduced to sets of 52 normalized region volumes for each subject by using a neuroanatomic atlas. Normalized regional volumes of the control and patient groups were compared by using Student t-test, and age correlation of each region volume was calculated for the two groups. All results were corrected for multiple comparisons by using permutation testing. We used a classifier based on support vector machines and a feature selection method to determine our ability to discriminate brains of controls from those of patients. RESULTS: Analysis of normalized region volumes shows enlargement of the third ventricle in patients. The age-correlation study showed a significant positive correlation in the third ventricle and right thalamus of controls, but not patients. Using an average of 6.5 features, our classifier was able to correctly identify 72% of patients and 70% of controls. CONCLUSION: In addition to enlargement of the third ventricle, brains of patients with schizophrenia show a different pattern of age-related changes.

Adult↗

PubMed2025

Gestational vitamin D concentration and child cognitive development: a longitudinal cohort study in the Environmental influences on Child Health Outcomes Program.

BACKGROUND: Low vitamin D concentrations are common-especially among those with darker pigmented skin-and are frequently observed during pregnancy. Given its important role in brain development, inadequate gestational vitamin D may impair child cognitive development. OBJECTIVES: We aimed to evaluate associations of gestational vitamin D concentrations with childhood cognitive scores, explore whether this relationship differs by self-reported race, and examine sensitive exposure windows within pregnancy. METHODS: This prospective cohort study included 912 mother-child dyads (37.3% Black, 52.3% White) from the Environmental influences on Child Health Outcomes program. 25-hydroxyvitamin D [25(OH)D] concentrations were measured in prenatal or cord blood collected between 4 and 42 wk gestation (median: 23 wk). Children's cognition was assessed at ages 7-12 y using the NIH Toolbox Cognition Battery. Relationships of 25(OH)D and cognitive scores were examined using mixed-effects linear models adjusted for confounders. Potential sensitive periods were explored by estimating population 25(OH)D patterns across gestation for varying levels of the cognitive outcomes. RESULTS: Mean gestational 25(OH)D was 23.8 ng/mL (SD: 10.0 ng/mL). Each 10-ng/mL increase was associated with greater overall (β: 1.11; 95% CI: 0.08, 2.14) and fluid cognition scores (β: 1.21; 95% CI: 0.07, 2.34), but not crystallized cognition. Although these associations were not significantly modified by self-reported race, associations appeared stronger in children of Black mothers (β: 2.99; 95% CI: 0.82, 5.16) than those in non-Black mothers (β: 0.43; 95% CI: -0.93, 1.78) for fluid cognition. Early pregnancy may be a critical exposure period, evidenced by the greatest divergence in the pattern of 25(OH)D during this period between the mothers of children in the 90th and those in the 10th percentiles of cognitive outcomes. CONCLUSIONS: Gestational 25(OH)D concentrations were positively associated with cognitive scores, especially in children of Black mothers. Given higher deficiency risk among Black women, vitamin D repletion before or in early pregnancy may be an important strategy for reducing racial disparities in child neurodevelopment.

Humans↗