Biomedical subjects

Daniel C Javitt

Publications and source records attributed to Daniel C Javitt.

At least 19 recordsLinked to original sources

PubMed2006

Boundary completion is automatic and dissociable from shape discrimination.

Normal visual perception readily overcomes suboptimal or degraded viewing conditions through perceptual filling-in processes, enhancing object recognition and discrimination abilities. This study used visual evoked potential (VEP) recordings in conjunction with electrical neuroimaging analyses to determine the spatiotemporal brain dynamics of boundary completion and shape discrimination processes in healthy humans performing the so-called "thin/fat" discrimination task (Ringach and Shapley, 1996) with stimuli producing illusory contours. First, results suggest that boundary completion processes occur independent of subjects' accuracy on the discrimination task. Modulation of the VEP to the presence versus absence of illusory contours [the IC effect (Murray et al., 2002)] was indistinguishable in terms of response magnitude and scalp topography over the 124-186 ms poststimulus period, regardless of whether task performance was correct. This suggests that failure on this discrimination task is not primarily a consequence of failed boundary completion. Second, the electrophysiological correlates of thin/fat shape discrimination processes are temporally dissociable from those of boundary completion, occurring during a substantially later phase of processing (approximately 330-406 ms). The earlier IC effect was unaffected by whether the perceived contour produced a thin or fat shape. In contrast, later time periods of the VEP modulated according to perceived shape only in the case of stimuli producing illusory contours, but not for control stimuli for which performance was at near-chance levels. Collectively, these data provide further support for a multistage model of object processing under degraded viewing conditions.

Adult↗

PubMed2006

Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments.

Visual processing deficits are an integral component of schizophrenia and are sensitive predictors of schizophrenic decompensation in healthy adults. The primate visual system consists of discrete subcortical magnocellular and parvocellular pathways, which project preferentially to dorsal and ventral cortical streams. Subcortical systems show differential stimulus sensitivity, while cortical systems, in turn, can be differentiated using surface potential analysis. The present study examined contributions of subcortical dysfunction to cortical processing deficits using high-density event-related potentials. Event-related potentials were recorded to stimuli biased towards the magnocellular system using low-contrast isolated checks in Experiment 1 and towards the magnocellular or parvocellular system using low versus high spatial frequency (HSF) sinusoidal gratings, respectively, in Experiment 2. The sample consisted of 23 patients with schizophrenia or schizoaffective disorder and 19 non-psychiatric volunteers of similar age. In Experiment 1, a large decrease in the P1 component of the visual event-related potential in response to magnocellular-biased isolated check stimuli was seen in patients compared with controls (F = 13.2, P = 0.001). Patients also showed decreased slope of the contrast response function over the magnocellular-selective contrast range compared with controls (t = 9.2, P = 0.04) indicating decreased signal amplification. In Experiment 2, C1 (F = 8.5, P = 0.007), P1 (F = 33.1, P < 0.001) and N1 (F = 60.8, P < 0.001) were reduced in amplitude to magnocellular-biased low spatial frequency (LSF) stimuli in patients with schizophrenia, but were intact to parvocellular-biased HSF stimuli, regardless of generator location. Source waveforms derived from inverse dipole modelling showed reduced P1 in Experiment 1 and reduced C1, P1 and N1 to LSF stimuli in Experiment 2, consistent with surface waveforms. These results indicate pervasive magnocellular dysfunction at the subcortical level that leads to secondary impairment in activation of cortical visual structures within dorsal and ventral stream visual pathways. Our finding of early visual dysfunction is consistent with and explanatory of classic literature showing subjective complaints of visual distortions and is consistent with early visual processing deficits reported in schizophrenia. Although deficits in visual processing have frequently been construed as resulting from failures of top-down processing, the present findings argue strongly for bottom-up rather than top-down dysfunction at least within the early visual pathway. Deficits in magnocellular processing in this task may reflect more general impairments in neuronal systems functioning, such as deficits in non-linear amplification and may thus represent an organizing principle for predicting neurocognitive dysfunction in schizophrenia.

Adult↗

PubMed2006

Functional anatomy and interaction of fast and slow visual pathways in macaque monkeys.

We measured the timing, areal distribution, and laminar profile of fast, wavelength-insensitive and slower, wavelength-sensitive responses in V1 and extrastriate areas, using laminar current-source density analysis in awake macaque monkeys. There were 3 main findings. 1) We confirmed previously reported significant ventral-dorsal stream latency lags at the level of V4 (V4 mean = 38.7 ms vs. middle temporal mean = 26.9 ms) and inferotemporal cortex (IT mean = 43.4 ms vs. dorsal bank of the superior temporal sulcus mean = 33.9 ms). 2) We found that wavelength-sensitive inputs in areas V1, V4, and IT lagged the wavelength-insensitive responses by significant margins; this lag increased over successive levels of the system. 3) We found that laminar activation profiles in V4 and IT were inconsistent with "feedforward" input through the ascending ventral cortical pathway; the likely alternative input routes include both lateral inputs from the dorsal stream and direct inputs from nonspecific thalamic neurons. These findings support a "Framing" Model of ventral stream visual processing in which rapidly conducted inputs, mediated by one or more accessory pathways, modulate the processing of more slowly conducted feedforward inputs.

Animals↗

PubMed2006

A new dimension of sensory dysfunction: stereopsis deficits in schizophrenia.

BACKGROUND: Schizophrenia is a neurocognitive disorder with a wide range of cognitive and sensory impairments. Early visual processing has been shown to be especially impaired. This article investigates the integrity of binocular depth perception (stereopsis) in schizophrenia. METHODS: Seventeen schizophrenia patients and 19 healthy control subjects were compared on the Graded Circles Stereo Test. Results of stereoacuity were compared between patients and control subjects using t test. RESULTS: Schizophrenia patients demonstrated significantly (p = .006) reduced stereoacuity (mean = 142 arcseconds) versus control subjects (mean = 55 arcseconds). At the normative level for adults, patients performed below chance. CONCLUSIONS: These findings demonstrate an impairment of binocular depth perception and further confirm deficits of early visual processing in schizophrenia. Findings are discussed in context of magnocellular/dorsal stream processing with implications for visual processing and cognitive deficits.

Adult↗

PubMed2006

Reading impairment and visual processing deficits in schizophrenia.

Individuals with schizophrenia show magnocellular visual pathway abnormalities similar to those described in dyslexia, predicting that reading disturbance should be a common concomitant of schizophrenia. To date, however, reading deficits have not been well established, and, in fact, reading is often thought to be normal in schizophrenia based upon results of tests such as the WRAT, which evaluate single word reading. This study evaluated "real world" reading ability in schizophrenia, relative to functioning of the magnocellular visual pathway. Standardized psychoeducational reading tests and contrast sensitivity measures were administered to 19 patients and 10 controls. Analyses of between group differences were further refined by classification of participants into reading vs. non-reading impaired groups using a priori and derived theoretical models. Patients with schizophrenia, as a group, showed highly significant impairments in reading (p<0.04-p<0.001), with particular deficits on tests of rate, comprehension and phonological awareness. Between 21% and 63% of patients met criteria for dyslexia depending upon diagnostic model vs. 0-20% of the controls. The degree of deficit correlated significantly with independent measures of magnocellular dysfunction. Reading impairment in schizophrenia reaches the level of dyslexia and is associated with compromised magnocellular processing as hypothesized. Findings related to symptoms, functioning and recommendations for reading ability assessment are discussed.

Adolescent↗

PubMed2006

Do you see what I am saying? Exploring visual enhancement of speech comprehension in noisy environments.

Viewing a speaker's articulatory movements substantially improves a listener's ability to understand spoken words, especially under noisy environmental conditions. It has been claimed that this gain is most pronounced when auditory input is weakest, an effect that has been related to a well-known principle of multisensory integration--"inverse effectiveness." In keeping with the predictions of this principle, the present study showed substantial gain in multisensory speech enhancement at even the lowest signal-to-noise ratios (SNRs) used (-24 dB), but it was also evident that there was a "special zone" at a more intermediate SNR of -12 dB where multisensory integration was additionally enhanced beyond the predictions of this principle. As such, we show that inverse effectiveness does not strictly apply to the multisensory enhancements seen during audiovisual speech perception. Rather, the gain from viewing visual articulations is maximal at intermediate SNRs, well above the lowest auditory SNR where the recognition of whole words is significantly different from zero. We contend that the multisensory speech system is maximally tuned for SNRs between extremes, where the system relies on either the visual (speech-reading) or the auditory modality alone, forming a window of maximal integration at intermediate SNR levels. At these intermediate levels, the extent of multisensory enhancement of speech recognition is considerable, amounting to more than a 3-fold performance improvement relative to an auditory-alone condition.

Adolescent↗

PubMed2006

Theory of Mind (ToM) and counterfactuality deficits in schizophrenia: misperception or misinterpretation?

BACKGROUND: Theory of Mind (ToM) refers to the ability to infer another person's mental state based upon interactional information. ToM deficits have been suggested to underlie crucial aspects of social interaction failure in disorders such as autism and schizophrenia, although the development of paradigms for demonstrating such deficits remains an ongoing area of research. Recent studies have explored the use of sarcasm perception, in which subjects must infer an individual's sincerity or lack thereof, as a 'real-life' index of ToM ability, and as an index of functioning of specific right hemispheric structures. Sarcastic detection ability has not previously been studied in schizophrenia, although patients have been shown to have deficits in ability to decode emotional information from speech ('affective prosody'). METHOD: Twenty-two schizophrenia patients and 17 control subjects were tested on their ability to detect sarcasm from spoken speech as well as measures of affective prosody and basic pitch perception. RESULTS: Despite normal overall intelligence, patients performed substantially worse than controls in ability to detect sarcasm (d=2.2), showing both decreased sensitivity (A') in detection of sincerity versus sarcasm and an increased bias (B'') toward sincerity. Correlations across groups revealed significant relationships between impairments in sarcasm recognition, affective prosody and basic pitch perception. CONCLUSIONS: These findings demonstrate substantial deficits in ability to infer an internal subjective state based upon vocal modulation among subjects with schizophrenia. Deficits were related to, but were significantly more severe than, more general forms of prosodic and sensorial misperception, and are consistent with both right hemispheric and 'bottom-up' theories of the disorder.

Adult↗

PubMed2006

Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder.

BACKGROUND: Compounds that reduce N-methyl-d-aspartate receptor (NMDAR) function, including NMDAR antagonists and partial agonists at the NMDAR-associated glycine (GLY) site, may act as antidepressants. The antibiotic drug d-cycloserine (DCS) acts as a partial agonist at the NMDAR-GLY site. Preclinical and clinical data suggest that at dosages >or=100 mg/day DCS acts as a functional NMDAR antagonist and may have antidepressant effects. METHODS: Twenty-two treatment resistant major depression patients participated in a double-blind, placebo-controlled 6-week crossover trial with 250 mg/day DCS added to their ongoing antidepressant medications. RESULTS: DCS treatment was well tolerated and resulted in symptom reductions. However, biweekly-performed clinical assessments, including the Hamilton Depression Rating Scale, Hamilton Rating Scale for Anxiety and Zung Self-Rating Depression Scale did not reveal statistically significant therapeutic advantages of DCS vs. placebo adjuvant treatment. LIMITATIONS: Small sample, uneven treatment resistance criteria across subjects. The exposure to DCS (dose/length of treatment) may not have been sufficient. CONCLUSIONS: This exploratory study represents the first attempt to assess the effects of a NMDAR-GLY site partial agonist in depression treatment. The findings and limitations of this study should be taken into account in the planning of future clinical trials with NMDAR modulators in depression.

Adult↗

PubMed2006

Changing plans: neural correlates of executive control in monkey and human frontal cortex.

Changing plans depends on executive control, the orchestration of behavior based on knowledge of both goal and context. Dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) cortices are clearly involved in these processes. Intracranial recordings in these regions were obtained from a monkey performing an executive control-challenging task that is widely used in clinic and laboratory to assess the integrity of cognitive function, the AX version of the continuous performance task (AX-CPT), and directly compared to scalp-recorded evoked potentials in humans. In this task the subject presses a button when detecting a frequent cue-target probe sequence in a stream of letters presented on a computer screen, and withholds response following incorrect sequences. Thus correct performance requires correct encoding of cue and probe instruction and inhibitory control. Intracranial recordings showed that DLPFC in the monkey was primarily activated by conditions that required inhibition of imminent action, as had been shown in human event-related potential (ERP) recordings. Different subregions of monkey ACC were activated primarily by either initiating or inhibiting action, whereas human ERP had shown ACC activation in both situations. We suggest that simultaneous activation of both types of subregions in conflict conditions may account the ubiquitous ACC activation observed with fMRI and ERP in those conditions.

Animals↗

PubMed2006

Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia.

BACKGROUND: Deficits in amplitudes of auditory event-related potentials (ERP) indexing preattentive, automatic (mismatch negativity, MMN) and controlled, attention-dependent (N2, P3) auditory information processing have been well described in chronic schizophrenia. Normal MMN, but deficient N2 and P3 have been reported in first-episode patients. No study has investigated these ERPs concurrently in first-episode patients; thus, reported differences in MMN, N2 and P3 generation may reflect differences in patient samples rather than genuine differences in abnormal generation of these ERPs. METHODS: We recorded MMN, N2 and P3 in 26 first-episode patients, 25 recent-onset patients within 1.5 to 5 years after first admission, 25 chronic patients and 39 healthy controls. RESULTS: Recent-onset and chronic, but not first-episode patients showed reduced MMN. However, among first-episode patients those with low premorbid educational achievement demonstrated significantly reduced MMN. All patient groups showed pronounced N2 deficits and, to a variable extent, abnormalities in P3 generation. CONCLUSIONS: Abnormalities in N2 and P3 generation appear to reflect premorbid neuropathology, whereas MMN deficits may index both ongoing disease processes associated with illness progression as well as premorbid neurocognitive impairment. ERPs may provide tools to assess static and progressive neuropathology in schizophrenia. These findings need confirmation in longitudinal studies.

Acoustic Stimulation↗

PubMed2006

Neurocognitive and symptom correlates of daily problem-solving skills in schizophrenia.

Functional outcome for individuals with schizophrenia has been associated with cognitive impairment. Deficits in attention, memory, speed of information processing and problem-solving skills affect independent functioning, vocational performance, and interpersonal functioning. This study investigated the relationship between neurocognitive functioning, clinical symptoms and daily problem-solving skills in seriously and persistently ill persons. Thirty-eight inpatients and outpatients were administered a neurocognitive battery for attention, working memory, processing speed, perceptual organization, and executive functioning; and semi-structured clinical interviews using the BPRS and SANS. Estimates of daily problem-solving skills were obtained using the relevant factor subscale from the Independent Living Scales (ILS-PB). Daily problem-solving skills were significantly correlated with negative symptoms, processing speed, verbal memory, and working memory scores. A regression model using an enter method suggests that working memory and negative symptoms are significant predictors of daily problem-solving skills and account for 73.2% of the variance. Further analyses demonstrate that daily problem-solving skills and negative symptoms were significantly different for inpatients and outpatients and significantly correlated with community status. The findings suggest the ILS-PB has utility as a proxy measure for assessing real-world functioning in schizophrenia.

Activities of Daily Living↗

PubMed2006

Early visual sensory deficits as endophenotypes for schizophrenia: high-density electrical mapping in clinically unaffected first-degree relatives.

CONTEXT: The imperative to establish so-called endophenotypes-quantifiable measures of risk for neurological dysfunction-is a growing focus of research in schizophrenia. Electrophysiological markers of sensory processing, observable in human event-related potentials, hold great promise in this regard, lying closer to underlying physiology than descriptive clinical diagnostic tests. OBJECTIVE: Early visual processing deficits, as measured by clear amplitude reductions in the occipital P1 component of the visual event-related potential, have been repeatedly demonstrated in patients with schizophrenia. However, before P1 amplitude may be considered as an endophenotypic marker for schizophrenia, it is necessary to establish its sensitivity to genetic liability. DESIGN, SETTING, AND PARTICIPANTS: Event-related potential responses to simple visual isolated-check stimuli were examined in 25 clinically unaffected first-degree relatives of patients with schizophrenia and 15 DSM-IV-diagnosed schizophrenia probands and compared with responses from 26 healthy, age-matched control subjects. Using high-density electrical scalp recordings, between-groups analysis assessed the integrity of the visual P1 component across the 3 groups. The study was conducted at St Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland. RESULTS: Substantially reduced P1 amplitude was demonstrated in both relatives and probands compared with controls with topographical mapping and inverse source analysis localizing this deficit largely to midline regions in early visual sensory cortices and regions of the dorsal visual stream. Additional later differences between these groups, where the relatives actually show larger amplitude responses, may point toward compensatory mechanisms at play in relatives. CONCLUSIONS: Our findings demonstrate a deficit in early visual processing in clinically unaffected first-degree relatives of patients with schizophrenia, providing evidence that this deficit may serve as a genetic marker for this disorder. The efficacy of using P1 amplitude as an endophenotype is underscored by the observation of a large effect size (d=0.9) over scalp sites where the deficit was maximal.

Adolescent↗

PubMed2006

Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients.

PURPOSE OF REVIEW: Current treatments for schizophrenia target the dopamine system. Developments of new treatments that target the glutamate system, however, are under progress, in particular, for the N-methyl-D-aspartate-type glutamate receptor. Compared with dopaminergic treatments, these treatments may show improved efficacy in the treatment of persistent negative symptoms. RECENT FINDINGS: During the past year, clinical trials have been published with several agonists at the glycine site of the N-methyl-D-aspartate receptor, including glycine, D-serine, D-alanine and with the glycine transport inhibitor, sarcosine. Studies published during the past year indicate highly significant beneficial effects on negative symptoms when these compounds are added to both conventional and newer atypical antipsychotics in efficacy models although an effectiveness trial of current formulations of glycine and D-cycloserine failed to show an overall benefit. Relevant issues across studies may include the compound chosen, its formulation and tolerability, populations studied, and the nature and dose of the base antipsychotic treatment. SUMMARY: The present findings continue to support the use of N-methyl-D-aspartate/glycine site agonists as potential new treatments for persistent negative symptoms of schizophrenia. Ongoing work with novel compounds and new formulations may assist in the translation of these advances into clinic-ready pharmacotherapies.

Antimetabolites↗

PubMed2006

Preattentively grouped tones do not elicit MMN with respect to each other.

To promote preattenive grouping of two sets of tones, one set of tones with a combination of frequency and ear of delivery was intermixed with another set of tones with a different combination of frequency and ear of delivery. The ERPs elicited by tones delivered to one ear that were preceded by three or four tones delivered in a row to the other ear were associated with an enhanced N1, due to the changes in frequency and ear of delivery with respect to the immediately preceding tones. However, no mismatch negativity (MMN) was obtained, even though these tones differed from the previious tones on the two dimensions of frequency and ear of delivery. The data were interpreted to signify that preattentively grouped sets of tones do not elicit MMN with respect to one another. This implies that once acoustic input has been preattentively grouped, the MMN system is dedicated to detecting changes that occur within but not between preattentively grouped stimuli.

Acoustic Stimulation↗

PubMed2006

Voxelwise correlational analyses of white matter integrity in multiple cognitive domains in schizophrenia.

Patients with schizophrenia show deficits in several neurocognitive domains. However, the relationship between white matter integrity and performance in these domains is poorly understood. The authors conducted neurocognitive testing and diffusion tensor imaging in 25 patients with schizophrenia. Performance was examined for tests of verbal declarative memory, attention, and executive function. Relationships between fractional anisotropy and cognitive performance were examined by using voxelwise correlational analyses. In each case, better performance on these tasks was associated with higher levels of fractional anisotropy in task-relevant regions.

Adult↗

PubMed2006

Visual white matter integrity in schizophrenia.

OBJECTIVE: Patients with schizophrenia have visual-processing deficits. This study examines visual white matter integrity as a potential mechanism for these deficits. METHOD: Diffusion tensor imaging was used to examine white matter integrity at four levels of the visual system in 17 patients with schizophrenia and 21 comparison subjects. The levels examined were the optic radiations, the striate cortex, the inferior parietal lobule, and the fusiform gyrus. RESULTS: Schizophrenia patients showed a significant decrease in fractional anisotropy in the optic radiations but not in any other region. CONCLUSIONS: This finding indicates that white matter integrity is more impaired at initial input, rather than at higher levels of the visual system, and supports the hypothesis that visual-processing deficits occur at the early stages of processing.

Adult↗

PubMed2005

Magnocellular contributions to impaired motion processing in schizophrenia.

Patients with schizophrenia show impairments in motion processing, along with deficits in lower level processing primarily involving the magnocellular visual pathway. The present study investigates potential magnocellular contributions to impaired motion processing in schizophrenia using a combined neurophysiological and behavioral approach. As compared to prior motion studies in schizophrenia, thresholds were determined for both incoherent and coherent visual motion. In this study, velocity discrimination thresholds were measured for schizophrenia patients (n=14) and age-matched normal control subjects (n=16) using a staircase procedure. Early visual processing was evaluated using steady-state visual evoked potentials (ssVEP), with stimuli biased toward activation of either the magnocellular or parvocellular visual pathways through luminance contrast manipulation. Patients with schizophrenia showed poor velocity discrimination for both incoherent and coherent motion, with no significant group x task interaction. Further, when coherent motion performance was measured at individually determined incoherent motion thresholds, accuracy levels for patients were similar to controls, also indicating similarity of deficit for incoherent vs. coherent motion discrimination. Impairments in velocity discrimination correlated significantly with reduced amplitude of ssVEP elicited by magnocellular -- but not parvocellular -- selective stimuli. This study demonstrates that deficits in motion processing in schizophrenia are significantly related to reduced activation of the magnocellular visual system. Further, this study supports and extends prior reports of impaired motion processing in schizophrenia, and indicates significant bottom-up contributions to higher-order cognitive impairments.

Adult↗

PubMed2005

Spatiotemporal dynamics of human object recognition processing: an integrated high-density electrical mapping and functional imaging study of "closure" processes.

Humans are capable of recognizing objects, often despite highly adverse viewing conditions (e.g., occlusion). The term "perceptual closure" has been used to refer to the neural processes responsible for "filling-in" missing information in the visual image under such conditions. Closure phenomena have been linked to a group of object recognition areas, the so-called lateral-occipital complex (LOC). Here, we investigated the spatiotemporal dynamics of perceptual closure processes by coregistering data from high-density electrical recordings (ERPs) and functional magnetic resonance imaging (fMRI) while subjects participated in a perceptual closure task. Subjects were presented with highly fragmented images and control scrambled images. Fragmented images were calibrated to be 'just' recognizable as objects (that is, perceptual closure was necessary), whereas the scrambled images were unrecognizable. Comparison of responses to these two stimulus classes revealed the neural processes underlying perceptual closure. fMRI revealed an object recognition system that mediates these closure processes, the core of which consists of the LOC regions. ERP recordings resulted in the well-characterized N(CL) component (for negativity associated with closure), a robust relative negativity over bilateral occipito-temporal scalp that occurs in the 230-400 ms timeframe. Our investigations further revealed an extended network of dorsal and frontal regions, also involved in perceptual closure processes. Inverse source analysis showed that the major generators of N(CL) localized to the identical regions within LOC revealed by the fMRI recordings and detailed the temporal dynamics across these LOC regions including interactions between LOC and these other nodes of the object recognition circuit.

Adult↗