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Daniel C Javitt

Publications and source records attributed to Daniel C Javitt.

At least 55 records · Page 3Linked to original sources
PubMed2004

Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis.

Phencyclidine (PCP), ketamine and other N-methyl-D-aspartate (NMDA) antagonists induce schizophrenia-like symptoms in normal volunteers, suggesting that endogenous dysfunction or dysregulation of NMDA receptors may contribute to the pathophysiology of schizophrenia. Glycine and D-cycloserine are potential treatments for persistent negative symptoms of schizophrenia. Seventeen patients were identified who participated in double-blind trials of both agents. Significant clinical improvement was observed during both trials. However, the degree of improvement was significantly larger during glycine, than D-cycloserine, treatment on both an individual subject and group level. Previous analyses have documented effectiveness of glycine, and to a lesser extent D-cycloserine, within separate patient populations. This analysis provides the first direct comparison of glycine and D-cycloserine effects within the same population, and suggests first, that NMDA agonists are effective in treatment of persistent negative symptoms of schizophrenia, and, second, that full agonists, such as glycine and D-serine, may be more effective than partial agonists such as D-cycloserine. Similar findings are apparent when data are considered from all trials with NMDA agonists performed to date. Overall, the findings indicate that agents which potentiate NMDA transmission may be therapeutically beneficial in treatment of persistent symptoms of schizophrenia.

Adult↗
PubMed2004

High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia.

BACKGROUND: Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA) receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia when used as adjuvants to conventional antipsychotics but possibly not to clozapine. In this study, we assessed whether high-dose glycine may also be therapeutically beneficial when added to olanzapine and risperidone treatment. METHODS: Seventeen olanzapine- or risperidone-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover treatment trial with.8 g/kg/day glycine added to their ongoing antipsychotic medication. Clinical assessments were performed biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored. RESULTS: Glycine treatment was well tolerated and resulted in a significant (p <.0001) 23% +/- 8% reduction in negative symptoms. Significant improvements were also registered in cognitive and positive symptoms. The negative symptoms improvement remained significant even following covariation for changes in other symptom clusters and extrapyramidal side effects. High posttreatment glycine serum levels significantly predicted (r =.60) clinical response. CONCLUSIONS: These findings indicate that the efficacy of olanzapine and risperidone may be augmented using high-dose adjuvant glycine treatment and suggest that these atypical antipsychotics may affect NMDA receptor-mediated neurotransmission differently than clozapine.

Adult↗
PubMed2004

Don't think of a white bear: an fMRI investigation of the effects of sequential instructional sets on cortical activity in a task-switching paradigm.

Using functional magnetic resonance imaging (fMRI), we investigated processes involved in switching between two ongoing tasks, thought to be paradigmatic of executive control processes. Subjects were considerably slower and less accurate when switching between two tasks than when repeatedly carrying out one task, so-called "switch costs." Switch costs, however, generally occur only when more than one task is associated with each stimulus type. This has led to the surmise that switch costs may be due largely to ongoing interference from previously learned stimulus-response (S-R) associations, which are no longer relevant for the task at hand. We used a paradigm that specifically assessed this hypothesis and investigated three stages. In Stage 1, a single task was carried out with each stimulus type; in Stage 2, a second novel task was introduced for each stimulus type; and in Stage 3, subjects reverted to carrying out solely the original tasks (as in Stage 1). In Stage 1, only one task was associated with each stimulus type, whereas two tasks were associated with each stimulus type in Stages 2 and 3. We compared images obtained during Stage 3 to those obtained during Stage 1 and show that during Stage 3, there was robust activation in the network of areas associated with the Stage 2 tasks, even though these tasks were no longer relevant. Our data strongly suggest that switch costs may derive largely from continued activation of areas associated with carrying out the now-irrelevant task(s). We posit that a large component of executive control processes involves resolution of competition between potentially relevant tasks. Our data also revealed widespread activation of a frontoparietal network of areas, and we discuss how this network might be involved in mediating this competition.

Adult↗
PubMed2004

Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists.

N-methyl-D-aspartate (NMDA) receptors may play a critical role in the pathophysiology of schizophrenia. In rodents, NMDA receptor antagonists, such as phencyclidine (PCP), induce dopaminergic dysregulation that resembles the pattern observed in schizophrenia. The present study investigates the degree to which concurrent treatment with NMDA modulators, such as glycine and the recently developed glycine transport antagonist N[3-(4"-fluorophenyl)-3-(4"-phenylphenoxy)propyl]sarcosine (NFPS) prevents dopaminergic dysregulation observed following chronic (3 months) or subchronic (2 weeks) PCP administration. Both chronic and subchronic treatment with PCP in the absence of glycine or NFPS led to significant potentiation of amphetamine-induced dopamine release in the prefrontal cortex and striatum, similar to that observed in schizophrenia. Treatment with either high-dose glycine or NFPS along with PCP prevented PCP effects. These findings demonstrate effective doses of glycine for use in animal models of schizophrenia, and support recent clinical studies showing the effectiveness of NMDA agonists in the treatment of persistent symptoms of schizophrenia.

Amphetamine↗
PubMed2004

Multisensory visual-auditory object recognition in humans: a high-density electrical mapping study.

Multisensory object-recognition processes were investigated by examining the combined influence of visual and auditory inputs upon object identification--in this case, pictures and vocalizations of animals. Behaviorally, subjects were significantly faster and more accurate at identifying targets when the picture and vocalization were matched (i.e. from the same animal), than when the target was represented in only one sensory modality. This behavioral enhancement was accompanied by a modulation of the evoked potential in the latency range and general topographic region of the visual evoked N1 component, which is associated with early feature processing in the ventral visual stream. High-density topographic mapping and dipole modeling of this multisensory effect were consistent with generators in lateral occipito-temporal cortices, suggesting that auditory inputs were modulating processing in regions of the lateral occipital cortices. Both the timing and scalp topography of this modulation suggests that there are multisensory effects during what is considered to be a relatively early stage of visual object-recognition processes, and that this modulation occurs in regions of the visual system that have traditionally been held to be unisensory processing areas. Multisensory inputs also modulated the visual 'selection-negativity', an attention dependent component of the evoked potential this is usually evoked when subjects selectively attend to a particular feature of a visual stimulus.

Adult↗
PubMed2004

Prefrontal-subcortical dissociations underlying inhibitory control revealed by event-related fMRI.

Using event-related fMRI, this study investigated the neural dynamics of response inhibition under fluctuating task demands. Fourteen participants performed a GO/NOGO task requiring inhibition of a prepotent motor response to NOGO events that occurred as part of either a Fast or Slow presentation stream of GO stimuli. We compared functional activations associated with correct withholds (Stops) required during the Fast presentation stream of stimuli to Stops required during the Slow presentation stream. A predominantly right hemispheric network was activated across conditions, consistent with previous studies. Furthermore, a functional dissociation of activations between conditions was observed. Slow Stops elicited additional activation in anterior dorsal and polar prefrontal cortex and left inferior parietal cortex. Fast Stops showed additional activation in a network that included right dorsolateral prefrontal cortex, insula and dorsal striatum. These results are discussed in terms of our understanding of the impact of preparation on the distributed network underlying response inhibition and the contribution of subcortical areas, such as the basal ganglia, to executive control processes.

Adult↗
PubMed2004

Predicting success: patterns of cortical activation and deactivation prior to response inhibition.

The present study investigated the relationships between attention and other preparatory processes prior to a response inhibition task and the processes involved in the inhibition itself. To achieve this, a mixed fMRI design was employed to identify the functional areas activated during both inhibition decision events and the block of trials following a visual cue introduced 2 to 7 sec prior (cue period). Preparing for successful performance produced increases in activation for both the cue period and the inhibition itself in the frontoparietal cortical network. Furthermore, preparation produced activation decreases in midline areas (insula and medial prefrontal) argued to be responsible for monitoring internal emotional states, and these cue period deactivations alone predicted subsequent success or failure. The results suggest that when cues are provided to signify the imminent requirement for behavioral control, successful performance results from a coordinated pattern of preparatory activation in task-relevant areas and deactivation of task-irrelevant ones.

Adult↗
PubMed2003

Magnocellular and parvocellular contributions to backward masking dysfunction in schizophrenia.

Patients with schizophrenia have repeatedly shown deficits in visual processing. These deficits have been well documented using visual backward masking (VBM). The VBM deficit in schizophrenia is thought to be due to aberrant interactions between magnocellular (M) and parvocellular (P) visual pathways. To date, no study has studied these claims with rigorous stimuli isolating M and P pathway responses. This study examined the function of each pathway and their interactions by creating M- and P-biased targets based on their known physiological properties. The M system responds to very low luminance contrast whereas the P system does not, and the P system responds to color contrast whereas the M system generally does not. Thus, to activate the P system, target letters and masks utilized color contrast, and to activate the M system, target letters and masks utilized very low luminance contrast. Four conditions were presented such that M- and P-biased targets were paired with both M- and P-biased masks. A significant Group x Mask Condition interaction was found when a P target was used in combination with an M or P mask, but not when an M target was used. In particular, schizophrenia patients needed significantly longer interstimulus intervals (ISIs) than controls to escape from masking in the P target/M mask condition, but not in any of the other three conditions. In addition, the critical stimulus durations (CSDs) for unmasked stimuli were significantly increased for both M and P targets in patients relative to controls. These findings demonstrate a significant impairment in M, but not P pathway, function in patients with schizophrenia. Furthermore, deficits of letter identification, including those of P targets, may also reflect impairment of the M pathway given the priming function of the dorsal stream.

Adult↗
PubMed2003

MRI study of white matter diffusion anisotropy in schizophrenia.

Diffusion tensor imaging (DTI) can provide information about brain white matter integrity. The results of DTI studies in schizophrenia are somewhat variable and could benefit from standardized image processing methods. Fourteen patients with schizophrenia or schizoaffective disorder and 14 healthy volunteers underwent DTI. Scans were analyzed using a rigorous voxelwise approach. The key dependent variable, fractional anisotropy, was lower for patients in the corpus callosum, left superior temporal gyrus, parahippocampal gyri, middle temporal gyri, inferior parietal gyri, medial occipital lobe, and the deep frontal perigenual region. Regions showing reduced white matter fractional anisotropy are known to be abnormal in schizophrenia. The voxelwise method used in the current study can provide the basis for hypothesis-driven research.

Adult↗
PubMed2003

Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys.

RATIONALE: Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating, which occurs across species and is deficient in severe neuropsychiatric disorders such as schizophrenia. In monkeys, as in rodents, phencyclidine (PCP) induces schizophrenia-like deficits in PPI. In rodents, in general, typical antipsychotics (e.g. haloperidol) reverse PPI deficits induced by dopamine (DA) agonists (e.g. apomorphine), but not those induced by N-methyl- d-aspartate (NMDA) receptor antagonists [e.g. phencyclidine (PCP)], whereas atypical antipsychotics (e.g. clozapine) reverse PPI deficits induced by DA agonists and NMDA antagonists. However, some discrepancies exist with some compounds and strains of rodents. OBJECTIVES: This study investigated whether a typical (haloperidol, 0.035 mg/kg) and an atypical (clozapine, 2.5 mg/kg) antipsychotic could be distinguished in their ability to reverse PCP-induced deficits in PPI in eight monkeys ( Cebus apella). METHODS: First, haloperidol dose was determined by its ability to attenuate apomorphine-induced deficits in PPI. Then, haloperidol and clozapine were tested in eight monkeys with PCP-induced deficits of PPI. Experimental parameters were similar to standard human PPI procedures, with 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse 16 dB above the 70 dB background noise. RESULTS: Clozapine reversed PCP-induced PPI deficits. In contrast, haloperidol did not significantly attenuate PCP-induced PPI deficits even at doses that significantly attenuated apomorphine effects. CONCLUSIONS: In this primate model, clozapine was distinguishable from haloperidol by its ability to attenuate PCP-induced deficits in PPI. The results provide further evidence that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.

Acoustic Stimulation↗
PubMed2003

Visual backward-masking deficits in schizophrenia: relationship to visual pathway function and symptomatology.

Patients with schizophrenia have information processing deficits which can be measured using visual backward-masking (VBM) tasks. There are two types of visual pathways: transient and sustained. The former is more sensitive to low spatial frequency (LSF) and the latter to high spatial frequency (HSF) stimuli. It has been hypothesized that the VBM deficit in schizophrenia is due to an overactive transient channel response to the mask. To examine this hypothesis, patients with schizophrenia and comparison volunteers were tested on a traditional backward-masking task as well as on tasks that altered the mask to bias stimulation toward transient (LSF) or sustained (HSF) channels. Medication effects and relationship to symptomatology were also examined. Patients with schizophrenia showed a significant deficit on the traditional backward-masking task and were also significantly impaired on the LSF- and HSF-masking tasks, though a differential deficit was not found on the latter two tasks. A U-shaped function, indicative of masking by interruption, was found on the LSF- and HSF-masking tasks. Masking performance was not altered when the same patients were tested on and off medication, and performance was related to positive and negative symptoms. In conclusion, the finding of a deficit in patients with schizophrenia on tasks producing a U-shaped function suggests that an aberrant transient response to the mask is producing increased interruption of the sustained response to the target.

Adult↗
PubMed2003

Right hemisphere control of visuospatial attention: line-bisection judgments evaluated with high-density electrical mapping and source analysis.

The "line-bisection" task has proven an especially useful clinical tool for assessment of spatial neglect syndrome in neurological patients. Here, we investigated the neural processes involved in performing this task by recording high-density event-related potentials from 128 scalp electrodes in normal observers. We characterized a robust net negative potential from 170-400 ms poststimulus presentation that correlates with line-bisection judgments. Topographic mapping shows three distinct phases to this negativity. The first phase (approximately 170-190 ms) has a scalp distribution exclusively over the right parieto-occipital and lateral occipital scalp, consistent with generators in the region of the right temporo-parietal junction and right lateral occipital cortices. The second phase (approximately 190-240 ms) sees the emergence of a second negative focus over the right central parietal scalp, consistent with subsequent involvement of right superior parietal cortices. In the third phase (approximately 240-400 ms), the topography becomes dominated by this right central parietal negativity. Inverse source modeling confirmed that right hemisphere lateral occipital, inferior parietal, and superior parietal regions were the likeliest generators of the bulk of the activity associated with this effect. The line stimuli were also presented at three contrast levels (3, 25, and 100%) in order to manipulate both the latency of stimulus processing and the relative contributions from magnocellular and parvocellular inputs. Through this manipulation, we show that the line-bisection effect systematically tracks/follows the latency of the N1 component, which is considered a temporal marker for object processing in the ventral visual stream. This pattern of effects suggests that this task invokes an allocentric (object-based) form of visuospatial attention. Further, at 3% contrast, the line-bisection effect was equivalent to the effects seen at higher contrast levels, suggesting that parvocellular inputs are not necessary for successful performance of this task.

Adult↗
PubMed2003

Subchronic continuous phencyclidine administration potentiates amphetamine-induced frontal cortex dopamine release.

Functional dopaminergic hyperactivity is a key feature of schizophrenia. Etiology of this dopaminergic hyperactivity, however, is unknown. We have recently demonstrated that subchronic phencyclidine (PCP) treatment in rodents induces striatal dopaminergic hyperactivity similar to that observed in schizophrenia. The present study investigates the ability of PCP to potentiate amphetamine-induced dopamine release in prefrontal cortex (PFC) and nucleus accumbens (NAc) shell. Prefrontal dopaminergic hyperactivity is postulated to underlie cognitive dysfunction in schizophrenia. In contrast, the degree of NAc involvement is unknown and recent studies have suggested that PCP-induced hyperactivity in rodents may correlate with PFC, rather than NAc, dopamine levels. Rats were treated with 5-20 mg/kg/day PCP for 3-14 days by osmotic minipump. PFC and NAc dopamine release to amphetamine challenge (1 mg/kg) was monitored by in vivo microdialysis and HPLC-EC. Doses of 10 mg/kg/day and above produced serum PCP concentrations (50-150 ng/ml) most associated with PCP psychosis in humans. PCP-treated rats showed significant, dose-dependent enhancement in amphetamine-induced dopamine release in PFC but not NAc, along with significantly enhanced locomotor activity. Enhanced response was observed following 3-day, as well as 14-day, treatment and resolved within 4 days of PCP treatment withdrawal. These findings support the concept that endogenous NMDA receptor dysfunction could account for the pattern of dopaminergic dysfunction observed in schizophrenia, and suggest that even short duration abuse of PCP-like agents may greatly potentiate behavioral effects of psychostimulants in drug abuse situations. Finally, these studies provide a model system in which to evaluate effects of potential psychotherapeutic agents.

Amphetamine↗
PubMed2003

Changing plans: a high density electrical mapping study of cortical control.

High density electrical mapping was used to index event-related brain activity in subjects performing parametric variations of the "AX"-type continuous performance task (AX-CPT) that differentially challenge control, and informative control conditions. In the AX-CPT, subjects must use context, created by a cue stimulus, to guide response to a target. Diseases such as schizophrenia and attention deficit hyperactivity disorder (ADHD) are associated with impaired AX-CPT performance. Event-related potentials (ERP) were analyzed as a function of both global and local stimulus context. The topographical analysis revealed that well-defined ERP are elicited under conditions where subjects must override a prepotent response. Activation patterns related to overriding a prepotent response (Go to No-Go) differed markedly from those associated with overriding a prepotent non-response (No-Go to Go). Dipole source mapping suggested that withholding a prepotent response is reflected primarily in anterior cingulate/dorsolateral prefrontal cortex activity during the 350-450 ms latency range following presentation of the No-Go. In contrast, preparing to respond is reflected in parietal (including area BA 40) activity during the same latency range, followed by a prolonged frontal negativity (contingent negative variation; CNV). Similar patterns of activation were observed whether the changes in preparation were triggered by cue or target stimuli, though target-elicited potentials peaked earlier.

Adolescent↗
PubMed2002

A novel alanine-insensitive D-serine transporter in rat brain synaptosomal membranes.

D-Serine is an endogenous modulator of brain N-methyl-D-aspartate receptors. This study investigates serine transport in brain synaptosomal fractions. Saturable, temperature-dependent uptake of both D- and L-[3H]serine was observed. Alanine was only partially effective in blocking transport, arguing against involvement of system ASC. Inhibitors of the systems A, L and GLY were also ineffective. Saturation studies suggested a submillimolar K(m) for both D- and L-serine. These data suggest the presence of a novel serine transport system in rodent synaptosomes.

Alanine↗
PubMed2002

The spatiotemporal dynamics of illusory contour processing: combined high-density electrical mapping, source analysis, and functional magnetic resonance imaging.

Because environmental information is often suboptimal, visual perception must frequently rely on the brain's reconstruction of contours absent from retinal images. Illusory contour (IC) stimuli have been used to investigate these "filling-in" processes. Intracranial recordings and neuroimaging studies show IC sensitivity in lower-tier area V2, and to a lesser extent V1. Some interpret these data as evidence for feedforward processing of IC stimuli, beginning at lower-tier visual areas. On the basis of lesion, visual evoked potentials (VEP), and neuroimaging evidence, others contend that IC sensitivity is a later, higher-order process. Whether IC sensitivity seen in lower-tier areas indexes feedforward or feedback processing remains unresolved. In a series of experiments, we addressed the spatiotemporal dynamics of IC processing. Centrally presented IC stimuli resulted in early VEP modulation (88-100 msec) over lateral-occipital (LOC) scalp--the IC effect. The IC effect followed visual response onset by 40 msec. Scalp current density topographic mapping, source analysis, and functional magnetic resonance imaging results all localized the IC effect to bilateral LOC areas. We propose that IC sensitivity described in V2 and V1 may reflect predominantly feedback modulation from higher-tier LOC areas, where IC sensitivity first occurs. Two additional observations further support this proposal. The latency of the IC effect shifted dramatically later (approximately 120 msec) when stimuli were laterally presented, indicating that retinotopic position alters IC processing. Immediately preceding the IC effect, the VEP modulated with inducer eccentricity--the configuration effect. We interpret this to represent contributions from global stimulus parameters to scene analysis. In contrast to the IC effect, the topography of the configuration effect was restricted to central parieto-occipital scalp.

Adult↗
PubMed2002

Impaired visual object recognition and dorsal/ventral stream interaction in schizophrenia.

BACKGROUND: Schizophrenia is associated with well-documented deficits in high-order cognitive processes such as attention and executive functioning. The integrity of sensory-level processing, however, has been evaluated only to a limited degree. Our study evaluated the ability of patients with schizophrenia to recognize complete objects based on fragmentary information, a process termed perceptual closure. Perceptual closure processes are indexed by closure negativity (N(cl)), a recently defined event-related potential (ERP) component that is generated within the visual association cortex. This study assessed the neural integrity of perceptual closure processes in schizophrenia by examining N(cl) generation. Generation of the preceding positive (P1) and negative (N1) ERP components was also examined. METHODS: We evaluated 16 patients with chronic schizophrenia and 16 healthy comparison subjects. Successively less fragmented images were presented during high-density ERP recording, which permitted the monitoring of brain activity during perceptual closure processes prior to object recognition. Analyses were performed at parieto-occipital and occipitotemporal sites consistent with dorsal and ventral stream generators of P1, N1, and N(cl). RESULTS: Patients with schizophrenia showed significant impairment in the ability to recognize fragmented objects, along with impaired generation of N(cl). The amplitude of visual P1 was significantly reduced, particularly over dorsal stream sites. In contrast, the generation of visual N1 was intact. CONCLUSIONS: Patients with schizophrenia are profoundly impaired in perceptual closure as indicated by both impaired performance and impaired N(cl) generation. The selective impairment in dorsal stream P1 is consistent with prior reports of impaired magnocellular processing in schizophrenia. By contrast, intact ventral N1 generation suggests that the initial stages of ventral stream processing are relatively preserved and that impaired magnocellular dorsal stream functioning in schizophrenia may lead to secondary dysregulation of ventral stream object recognition processing.

Adult↗