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Robert Freedman

Publications and source records attributed to Robert Freedman.

At least 37 records · Page 2Linked to original sources
PubMed2005

Behavioral and electrophysiological indices of temporal processing dysfunction in schizophrenia.

Timing deficits in schizophrenia have been noted in several behavioral studies. However, the involvement of mediating factors, such as inattention, has not been ruled out as contributing to these effects. Mismatch negativity (MMN), an electrophysiological measure, may provide a more direct index of stimulus processing ability in individuals with schizophrenia. The current study explored the relationship between behavioral time judgments and a time-based MMN paradigm. Participants were administered two MMN paradigms consisting of an "easy" or "difficult" deviant and an analogous behavioral measure of time processing. Matched against a healthy comparison group, patients exhibited decreased MMN amplitude on the "difficult" deviant interval only. However, on the behavioral paradigm, the patients made significantly more errors across all conditions. These results suggest that behavioral measures of time processing may reflect different processes than those captured by preattentive physiological measures in this population.

Acoustic Stimulation↗
PubMed2005

Early biomarkers of psychosis.

Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.

Biomarkers↗
PubMed2004

P50 sensory gating in adolescents from a pacific island isolate with elevated risk for schizophrenia.

BACKGROUND: Gating or inhibition of the P50 auditory evoked potential is a heritable neurobiological trait that has shown strong potential to serve as an endophenotype for schizophrenia. P50 sensory gating deficits have been found repeatedly in schizophrenic patients and in their unaffected first-degree relatives. P50 sensory gating has not yet been studied in high-risk (HR) offspring nor in prodromal adolescents. METHODS: A paired-stimulus auditory event-related potential paradigm was used to examine P50 sensory gating in 44 genetically HR adolescent offspring and 43 clinically HR prodromal adolescents with the same low genetic liability as a comparison group of 39 normal adolescents. RESULTS: Auditory sensory gating, as measured by the P50 ratio, was impaired in both genetically HR offspring and also in the clinically HR prodromal adolescents with no close affected relatives. In the genetically HR group, abnormal P50 sensory gating was found only in offspring who met criteria for the schizophrenia prodrome. CONCLUSIONS: Our findings suggest that P50 deficits are associated with the presence of prodromal symptoms, regardless of genetic risk. The results are consistent with the hypothesis that genetic liability in HR offspring increases risk for prodromal symptoms, and prodromal symptoms, in turn, increase risk for impaired sensory gating.

Adolescent↗
PubMed2004

Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.

RATIONALE AND OBJECTIVE: Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha(7) nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia. METHOD: This paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha(7) nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha(7) nicotinic receptor agonists may ameliorate some of these deficits. RESULTS: Impaired auditory sensory gating has been linked to the alpha(7) nicotinic receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha(7) nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha(7) nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures. CONCLUSION: Alpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.

Acoustic Stimulation↗
PubMed2004

Effects of nicotine on cognitive deficits in schizophrenia.

Several lines of evidence suggest a pathophysiological role for nicotinic receptors in schizophrenia. Activation by nicotine alters physiological dysfunctions, such as eye movement and sensory gating abnormalities, but effects on neuropsychological performance are just beginning to be investigated. Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and 10 nonsmokers were assessed following the administration of nicotine gum and placebo gum. The Repeatable Battery for the Assessment of Neuropsychological Status was administered. Nicotine affected only the Attention Index; there were no effects on learning and memory, language, or visuospatial/constructional abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent smokers after nicotine administration. The effects of nicotine in schizophrenia do not extend to all areas of cognition. Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers.

Adult↗
PubMed2004

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients.

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.

Acoustic Stimulation↗
PubMed2004

Neurobiology of smooth pursuit eye movement deficits in schizophrenia: an fMRI study.

OBJECTIVE: Smooth pursuit eye movements are abnormal in patients with schizophrenia. The investigators used functional magnetic resonance imaging (fMRI) to compare brain hemodynamic response during a smooth pursuit eye movement task in patients with schizophrenia and healthy comparison subjects. METHOD: Fourteen patients with schizophrenia and 14 healthy comparison subjects performed a smooth pursuit eye movement task while undergoing 1.5-T fMRI. Echo-planar images from the blocked design were evaluated with both a whole-brain random-effects analysis and a region-of-interest analysis. Smooth pursuit deficits were assessed outside the fMRI apparatus by using infrared oculography and were assessed during scanning by evaluating echo-planar time-series data from the eyes. RESULTS: Compared to the healthy subjects, the patients with schizophrenia exhibited greater activity in both posterior hippocampi and the right fusiform gyrus during smooth pursuit eye movements. The region-of-interest analysis revealed subtle activity deficits in frontal and occipital regions in the patients with schizophrenia. Smooth pursuit deficits in the subjects with schizophrenia included lower gain (eye velocity relative to target velocity) and a higher percentage of total eye movements due to anticipatory saccades, compared with the healthy subjects. CONCLUSIONS: The observed group differences are consistent with evidence for diminished inhibitory function in the hippocampus as well as for a disturbance in a frontotemporal network subserving smooth pursuit eye movements in schizophrenia.

Adult↗
PubMed2003

Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects.

The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first-degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal.

Base Sequence↗
PubMed2003

Schizophrenia.

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Adolescent↗
PubMed2003

Early postnatal development of sensory gating.

Sensory gating represents the nervous system's ability to inhibit responding to irrelevant environmental stimuli. In order to characterize the early development of acoustic sensory gating, suppression of auditory evoked potential component P1 (i.e. P50) in response to paired clicks was measured during REM sleep in healthy infants (1-4 months) that were without genetic risk for disrupted sensory gating function (i.e. having a relative with schizophrenia). As a group, the subjects exhibited significant response suppression. A correlation between increasing age and stronger response suppression was uncovered, even within this restricted age range. Parallel changes in sleep physiology could not be ruled out as the explanation for this change. Nevertheless, these results demonstrate that the neural circuits underlying sensory gating are functional very early in postnatal development.

Acoustic Stimulation↗
PubMed2003

The genetics of sensory gating deficits in schizophrenia.

Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain's normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the alpha-7-nicotinic receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.

Brain↗
PubMed2003

Sensory gating impairment associated with schizophrenia persists into REM sleep.

Physiological measures of sensory gating are increasingly used to study biological factors associated with attentional dysfunction in psychiatric and neurologic patient populations. The present study was designed to assess sensory gating during rapid eye movement (REM) sleep in patients with schizophrenia, a population bearing a genetic load for gating impairment. Auditory event-related potentials (ERPs) were recorded in response to paired clicks during separate waking and overnight sleep recording sessions in controls and schizophrenia patients. Suppression of ERP component P50 was significantly impaired in the patient group during both waking and REM sleep, whereas the difference between groups for N100 gating was dependent on state. These results suggest that REM sleep is an appropriate state during which to assess P50 gating in order to disentangle the effects of state and trait on sensory gating impairment in other clinical populations.

Acoustic Stimulation↗
PubMed2002

Development of the alpha7 nicotinic cholinergic receptor in rat hippocampal formation.

The alpha7 nicotinic receptor has been implicated in the regulation of a variety of developmental processes. The goal of the present study was to assess whether the alpha7 receptor might participate in the regulation of hippocampal ontogeny by describing the spatiotemporal development of alpha7 mRNA and alpha-bungarotoxin binding in rat hippocampal formation. Message for the alpha7 receptor was initially observed in the hippocampal neuroepithelium at embryonic day 13 and in the anlage of the hippocampal formation on embryonic day 14. Binding of alpha-bungarotoxin was initially seen on embryonic day 15 in the dorsal portion of the anlage of stratum oriens and stratum radiatum-lacunosum moleculare, but was never observed in the neuroepithelium. Dramatic elevations in both alpha7 mRNA and alpha-bungarotoxin binding were observed in most regions of the hippocampal formation neonatally. The levels of both alpha7 message and protein gradually decreased during the first three postnatal weeks to adult levels in most regions. The lack of alpha-bungarotoxin binding in the neuroepithelium suggests that the alpha7 receptor does not influence neurogenesis. The early appearance and complex, prolonged pattern of development of the alpha7 receptor suggest that it may influence processes as diverse as cell migration, dendritic elaboration and apoptosis during hippocampal maturation.

Acetylcholine↗
PubMed2002

Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism.

RATIONALE: Insufficient inhibitory processing of the P50 auditory evoked potential (AEP) is observed in most schizophrenia patients and is not improved by typical antipsychotic drugs, such as haloperidol. This inhibitory processing deficit is associated with a subnormal level of hippocampal alpha7 nicotinic receptors (nAChRs), and drugs that activate these receptors normalize the deficit. The atypical antipsychotic clozapine also normalizes this deficit in schizophrenia patients, but by an unknown mechanism. OBJECTIVE: Similar to schizophrenia patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 AEP, which is a rodent analogue of the human P50 AEP. The present study determined whether clozapine improved this deficit in DBA/2 mice, and by what mechanism. METHOD: Using a conditioning-testing paradigm with paired auditory stimuli to assess inhibitory P20-N40 AEP processing in DBA/2 mice, the effects of clozapine (0.1, 1, 3.33, or 10 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) were assessed. The effect of clozapine (1 mg/kg) was assessed alone and after pre-administration of either alpha-bungarotoxin, an alpha7 nAChR antagonist, or dihydro-beta-erythroidine, an alpha4beta2 nAChR antagonist. RESULTS: In a dose-dependent manner, clozapine improved the deficient inhibitory processing of the P20-N40 AEP normally exhibited by DBA/2 mice. Like alpha7 agonists, 1 mg/kg clozapine selectively increased the inhibition of the P20-N40 response to the second of paired auditory stimuli. The normalizing effect of 1 mg/kg clozapine was blocked by alpha-bungarotoxin, but not by dihydro-beta-erythroidine. Haloperidol did not improve DBA/2's deficient P20-N40 AEP processing. CONCLUSIONS: Clozapine improved the deficient inhibitory processing of the P20-N40 AEP in DBA/2 mice, apparently through stimulation of alpha7 nicotinic receptors. This effect was not shared by the typical antipsychotic haloperidol.

Acoustic Stimulation↗
PubMed2002

Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia.

OBJECTIVE: Decreased hippocampal volume is one of the hypothesized pathological features of schizophrenia, but it is not known if this abnormality is familially transmitted. The aim of this study was to measure the hippocampal volume of the parents of schizophrenic probands, in relationship to the apparent transmission of genetic risk. METHOD: Eighteen subjects from families consisting of a schizophrenic proband and two clinically unaffected parents were studied. Probands were compared to six control subjects, matched for age, sex, and educational level. The six families were selected so that only one parent had an ancestral family history of schizophrenia. The volumes of both hippocampi were measured by magnetic resonance imaging and adjusted for age and whole brain volume. RESULTS: The total hippocampal volumes of the parents with ancestral family history of schizophrenia were significantly larger than those of their schizophrenic offspring. CONCLUSIONS: This study suggests that decreased hippocampal volume in schizophrenia is not a familially transmitted abnormality. Rather, it appears that clinically unaffected parents who transmit apparent genetic risk for schizophrenia may have increased hippocampal volume, which may be a protective factor against the illness.

Adolescent↗