Biomedical subjects

Richard Coppola

Publications and source records attributed to Richard Coppola.

15 recordsLinked to original sources

PubMed2007

Complex relationship between BOLD signal and synchronization/desynchronization of human brain MEG oscillations.

Functional magnetic resonance imaging (fMRI) depends on the coupling of cerebral blood flow, energy demand, and neural activity. The precise nature of this interaction, however, is poorly understood. A positive correlation between BOLD-response and cortically generated local field potentials, which reflect the weighted average of synchronized dentrosomatic components of pyramidal synaptic signals, has been demonstrated. Likewise, positive BOLD-responses have been reported in conjunction with scalp-recorded synchronized electromagnetic activity by a number of groups. However, it is not yet clear how the opposite electromagnetic pattern, i.e. cortical desynchronization, is related to the BOLD signal. To address this question, we conducted a combined event-related fMRI and 275 sensor whole-head MEG study during identical visual two-choice reaction time task conditions in 10 human subjects. We found complex sequences of MEG-synchronization and desynchronization across a wide frequency range in the visual and motor area in close correspondence with "locales" of positive BOLD-responses. These results indicate that a correspondence of positive BOLD-responses is not exclusively found for cortical synchronization but also for desynchronization, suggesting that the relationship between BOLD signals and electromagnetic activity might be more complex than previously thought.

Adult↗

PubMed2006

Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment.

The purpose of this pilot study was to: (1) determine if regional brain volume change occurs in schizophrenia patients during very short periods of withdrawal from, or stable treatment with, antipsychotics, and; (2) compare results of region-of-interest (ROI) to voxel-based morphometry (VBM) methods. In two small groups of schizophrenic inpatients, magnetic resonance imaging was performed before and after antipsychotic withdrawal, and at two time points during stable chronic antipsychotic treatment. Regional brain volumes were measured using ROI methods. Grey matter volume was measured with VBM. The medication withdrawal group showed no effect of treatment state or antipsychotic type on regional brain volumes with ROI analysis, but effects of both treatment state and antipsychotic type on grey matter volume were observed with VBM in right middle frontal, right medial frontal, right and left superior frontal, right cingulate, and right superior temporal gyrii as well as in the right and left hippocampal gyrii. The chronic stable treatment group showed an effect of time on right caudate, left hippocampal, and total cerebrospinal fluid volumes with ROI analysis, while effects of both time and antipsychotic type were observed with VBM on grey matter volume in the left superior temporal lobe. No findings survived correction for multiple comparisons. A positive correlation between regional volume change and emerging psychopathology was demonstrated using ROI methods in the medication withdrawal group. Treatment state and emergent symptoms in schizophrenia patients were associated with regional volume change over very short time periods. Longitudinal regional brain volume change in schizophrenia patients is likely physiologic and therefore potentially reversible.

Adult↗

PubMed2006

Prefrontal electrophysiologic "noise" and catechol-O-methyltransferase genotype in schizophrenia.

BACKGROUND: Increased variability of stimulus-induced prefrontal electromagnetic activity ("noise") has been associated with genetic risk for schizophrenia. On the basis of animal experiments and computational models, we have predicted that this prefrontal "noise" phenotype would be related to variation in prefrontal dopamine (DA) signaling, which itself might be abnormal in schizophrenia. In the present study, the effect of a functional single nucleotide polymorphism (val(108/158)met) within the catechol-O-methyltransferase (COMT) gene on prefrontal "noise" was examined, because the COMT enzyme is involved in cortical synaptic dopamine metabolism and weakly predictive of risk for schizophrenia. METHODS: A Caucasian sample comprising 112 unrelated normal subjects, 83 schizophrenic probands, and 87 of their unaffected siblings was investigated, all of whom had measures of prefrontal "noise" estimated from event-related electroencephalogram during an auditory oddball task. RESULTS: The val(108/158)met genotype was significantly associated with prefrontal "noise"; homozygous Val-carriers had greatest prefrontal "noise" values; odds ratio (OR) = 2.37 (95% confidence interval [CI] 1.37-4.10), p = 003. The genotype-phenotype association was stronger when only considering male subjects with an OR = 3.37 (95% CI: 1.63-6.98), p = 002. CONCLUSIONS: The results suggest that COMT genotype impacts the level of prefrontal physiologic "noise."

Acoustic Stimulation↗

PubMed2006

The G72/G30 gene complex and cognitive abnormalities in schizophrenia.

A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p=0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p=0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.

Adult↗

PubMed2006

Large-scale visuomotor integration in the cerebral cortex.

Efficient visuomotor behavior depends on integrated processing by the visual and motor systems of the cerebral cortex. Yet, many previous cortical neurophysiology studies have examined the visual and motor modalities in isolation, largely ignoring questions of large-scale cross-modal integration. To address this issue, we analyzed event-related local field potentials simultaneously recorded from multiple visual, motor, and executive cortical sites in monkeys performing a visuomotor pattern discrimination task. The timing and cortical location of four aspects of event-related activities were examined: stimulus-evoked activation onset, stimulus-specific processing, stimulus category-specific processing, and response-specific processing. Activations appeared earliest in striate cortex and rapidly thereafter in other visual areas. Stimulus-specific processing began early in most visual cortical areas, some at activation onset. Early onset latencies were also observed in motor, premotor, and prefrontal areas, some as early as in striate cortex, but these early-activating frontal sites did not show early stimulus-specific processing. Response-specific processing began around 150 ms poststimulus in widespread cortical areas, suggesting that perceptual decision formation and response selection arose through concurrent processes of visual, motor, and executive areas. The occurrence of stimulus-specific and stimulus category-specific differences after the onset of response-specific processing suggests that sensory and motor stages of visuomotor processing overlapped in time.

Algorithms↗

PubMed2006

Instability of prefrontal signal processing in schizophrenia.

OBJECTIVE: Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phase-synchronization (i.e., an increased stimulus-related variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. METHOD: Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. RESULTS: In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a "fractionized" and unfocussed pattern of activation in patients. CONCLUSIONS: These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia.

Adult↗

PubMed2004

Prefrontal broadband noise, working memory, and genetic risk for schizophrenia.

OBJECTIVE: It has been suggested that increased variability of prefrontal physiological responses may represent a fundamental mechanism underlying frontal lobe deficits in schizophrenia. Increased response variability ("noise") is thought to result from impaired phase resetting of stimulus-induced dynamic changes of ongoing rhythmic oscillations (field potentials) generated in the apical dendrites of pyramidal neurons. In the present study, the authors explored whether this particular physiological abnormality predicts working memory performance and is related to the genetic risk for schizophrenia. METHOD: Prefrontal response variability of discrete frequency components was investigated across a broad frequency range (0.5-45.0 Hz) during processing of an oddball paradigm in patients with schizophrenia (N=66), their clinically unaffected siblings (N=115), and healthy comparison subjects (N=89). RESULTS: As hypothesized, prefrontal noise was negatively correlated with working memory performance across all subjects. In addition, it was observed that prefrontal noise possesses trait characteristics and is strongly associated with genetic risk for schizophrenia. CONCLUSIONS: Frontal lobe-related cognitive function depends on the ability to synchronize cortical pyramidal neurons, which is in part genetically controlled. Increased prefrontal "noise" is an intermediate phenotype related to genetic susceptibility for schizophrenia.

Adult↗

PubMed2003

Functional and effective frontotemporal connectivity and genetic risk for schizophrenia.

BACKGROUND: Functional neuroimaging and electrophysiologic studies have found disturbed frontotemporal interaction in schizophrenia. We sought to determine whether abnormalities of frontotemporal connectivity are trait markers of genetic risk for schizophrenia. METHODS: We investigated 64 schizophrenia patients, 79 of their clinically unaffected siblings, and 88 unrelated normal controls with an auditory oddball electroencephalogram (EEG) evoked potential paradigm. We measured: 1) frontotemporal event-related EEG-coherence (i.e. a measure of functional connectivity); and 2) we performed structural equation modeling of the effective connectivity between the frontal P300 and temporoparietal P300-amplitude. RESULTS: Schizophrenic patients and their siblings showed a reduction of frontotemporal coherence. At peak activation during the P300 time-window, a negative ("inhibitory") frontotemporal path coefficient was found in normal controls, whereas a positive coefficient was seen in schizophrenic patients with siblings being intermediate. Intra-class correlations between sib-pairs and relative risk estimates of the applied connectivity measures were non-significant. Topographic correlation matrix analyses suggested that the altered functional and effective frontotemporal connectivity indirectly reflect regional abnormalities of increased activation variance. CONCLUSIONS: Impaired interaction of the frontotemporal macro-circuit indirectly reflects genetically determined abnormalities of frontal and temporoparietal microcircuits. The reasons why frontotemporal connectivity appears to be a poor predictor of genetic risk for schizophrenia are discussed.

Adult↗

PubMed2003

P300 and genetic risk for schizophrenia.

BACKGROUND: We assessed the suitability of event-related potential frontal and temporoparietal P300 changes as intermediate phenotypes in genetic studies of schizophrenia. We applied a principal component analysis approach based on the notion that P300 abnormalities in siblings of schizophrenic patients may involve a widespread network of relatively weak cortical generators and because an earlier, smaller study that used a topographic analysis of covariance model did not show that localized P300 changes predict risk for schizophrenia. METHODS: P300 changes in 66 schizophrenic patients, 115 healthy siblings of schizophrenic patients, and 89 unrelated controls were studied during a standard auditory oddball paradigm. Principal components were calculated across electrodes, revealing frontal and temporoparietal components for latency and amplitude, respectively. For the frontal and temporoparietal P300 amplitude and latency components, the intraclass correlations (ICCs) between sib-pairs (pairs of unaffected siblings and schizophrenic index patients) and the relative risk ratios (lambda) were determined. RESULTS: Compared with controls, schizophrenic patients and their unaffected siblings showed significant reductions in the temporoparietal P300 amplitude component. Both groups were also characterized by a significantly higher frontal P300 amplitude component. Significant ICCs and increased relative risk ratios were found for the frontal (ICCU = 0.18; P =.04; lambda = 3.4) and temporoparietal (ICCU = 0.24; P =.01; lambda = 1.7) P300 amplitude components. CONCLUSIONS: Temporoparietal P300 amplitude reduction and frontal P300 amplitude increase seem to be quantitative phenotypes associated with increased risk of schizophrenia. Both measures may be useful for increasing the statistical power of genetic studies of schizophrenia.

Adolescent↗

PubMed2003

Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia.

BACKGROUND: Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. METHODS: Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol-O-methyltransferase (COMT) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. RESULTS: A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. CONCLUSIONS: A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition.

Adult↗

PubMed2003

In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia.

OBJECTIVE: Postmortem studies have implicated the central muscarinic acetylcholine system in schizophrenia. However, central muscarinic receptor availability has not previously been studied in vivo. Using [I-123]iodoquinuclidinyl benzilate ([(123)I]IQNB) single photon emission computed tomography (SPECT), the authors sought to compare the muscarinic receptor availability in vivo in unmedicated patients with schizophrenia and normal subjects. METHOD: Twelve medication-free patients with schizophrenia underwent an [(123)I]IQNB SPECT scan during approximate-equilibrium conditions. A group of 10 age- and gender-matched normal comparison subjects were given the same kind of scan under similar conditions. Regions of interest were analyzed in the cortex, basal ganglia, thalamus, and pons. Binding data were analyzed as nCi/ml tissue per mCi injected dose. RESULTS: Muscarinic receptor availability was significantly less in patients with schizophrenia than in normal subjects in all regions of interest except the pons. Reductions ranged from -33% in the caudate to -20% in the occipital cortex. Positive symptoms of schizophrenia correlated negatively with muscarinic receptor availability in the striatum and the frontal cortex. CONCLUSIONS: These results indicate a reduction in muscarinic acetylcholine receptor availability in vivo in unmedicated patients with schizophrenia, confirming results from postmortem studies and adding further evidence that the muscarinic system is involved in the pathophysiology of schizophrenia.

Adult↗

PubMed2002

Thalamic and caudate volumes in monozygotic twins discordantfor schizophrenia.

OBJECTIVE: The thalamus and caudate nucleus are key subcortical structures in the fronto-striato-thalamic pathways that have been implicated in the pathogenesis of schizophrenia. Previous studies have been inconsistent in identifying structural and functional abnormalities in these structures. However, methodologies in these studies have been unreliable and some have not adequately matched patients and controls. METHODS: Using algebraically-manipulated double-echomagnetic resonance (MR) images, we developed a reliable method to estimate caudate and thalamic volumes in a group of 13 monozygotic(MZ) twins; eight discordant for schizophrenia and five normal.Initially, volumes were measured on four image types: proton density(PD), T2-weighted, summed (PD + T2) and subtracted (PD-T2) to determine the most reliable method. RESULTS: There was a significant method by region interaction, where caudate volumes measured on PD images were significantly larger than those measured on T2-weighted images, while the opposite was found for thalamic volumes. However, there was no interaction of method by diagnosis. Test-retest reliability was highest for the summed images. Using summed images to measure the volumes of the caudate and thalamus in each twin, we found significantly increased caudate volumes in affected twins compared to their unaffected cotwins,but no significant difference in thalamic volume. CONCLUSIONS: Our results in a small sample of MZ twins discordant for schizophrenia do not support the presence of structural abnormalities in the thalamus. The findings in the caudate are consistent with previously reported effects of antipsychotic medication. We also report a reliable method for assessing the volumes of subcortical structures. However, volumetric estimates of brain structures may be dependent on which method is used and the structure being assessed. Such interactions need to be considered in future studies investigating brain structural abnormalities in schizophrenia and other disorders.

Adult↗

PubMed1983

Where is the noise in SDT pain assessment?

Many applications of sensory decision theory (SDT) to pain research have used discrimination as a measure of pain or sensory sensitivity. This belief is based on the classical SDT assumption that discrimination and criterion represent separation of sensory and decision processes. This assumed separation stems from a model where all noise or variability is part of the sensory transduction mechanism. We present an alternative formulation that allows for decision variability as well as variability in sensory transduction. This formulation documented by computer simulation shows that decision variability and sensory variability are indistinguishable and that any measure of discriminability is degraded by both. Thus discriminability is influenced by both sensory and non-sensory factors. There is no way of knowing if a drug-induced change in discriminability represents an analgesic effect or a change of the observer's ability to make consistent judgments.

Decision Theory↗

PubMed1981

Opiate pharmacology and individual differences. I. Psychophysical pain measurements.

A new electric stimulation pain assessment technique using the Tursky electrode and a non-parametric analysis of subjects ratings was found sensitive to aspirin, morphine and opiate antagonists in a series of double-blind cross-over trials in normal adults. Stable individual differences in pain sensitivity (off medication) were maintained on two testing sessions 7 months apart. Older individuals were less pain sensitive than younger individuals. Men were more insensitive than women under age 30. Together, these results suggest the empiric usefulness of this pain measurement technique.

Adolescent↗

PubMed1981

Opiate pharmacology and individual differences. II. Somatosensory evoked potentials.

Somatosensory evoked potentials (EPs) to stimuli ranging from barely perceptible to painful were recorded in 153 normal adults. Reliability of amplitude and amplitude/intensity slopes were demonstrated in 29 individuals tested twice, two or more weeks apart. In randomized, double-blind placebo controlled trials, both aspirin and morphine significantly diminished N120 component at high stimulus intensities. Age, sex and pharmacological effects paralleled those found with psychophysical techniques in part I of this study.

Adolescent↗