Biomedical subjects

Judith M Ford

Publications and source records attributed to Judith M Ford.

At least 19 recordsLinked to original sources

PubMed2006

MRI measurement of the uptake and retention of motexafin gadolinium in glioblastoma multiforme and uninvolved normal human brain.

PURPOSE: Motexafin gadolinium (MGd) is an investigational pharmaceutical with radiation enhancing properties. Magnetic Resonance Imaging (MRI) was used to measure brain and tumor MGd levels to evaluate (1) the degree to which MGd passes through the intact blood brain barrier, and (2) the retention of MGd in tumor in patients with glioblastoma multiforme (GBM). METHODS AND MATERIALS: MRI studies were performed on GBM patients who participated in a phase I clinical trial in which MGd was given during standard fractionated radiation therapy. MGd was administered daily (Monday to Friday) for five or 10 doses as a loading regimen, followed by three times per week dosing as a maintenance schedule. T1-weighted MRI was performed at intervals throughout the course of the MGd administration and radiation therapy in the 33 participating patients. Eleven patients had pre- and post-MGd scans, allowing for study of MGd's normal blood brain barrier penetration. Twenty-two patients had adequate residual tumor for measurements to evaluate MGd retention in tumor during the course of MGd and radiation administration. RESULTS AND CONCLUSIONS: The studies of uninvolved brain tissue support the conclusion that MGd does not cross the intact blood brain barrier in detectable quantities. The tumor study showed MGd uptake during loading and maintenance without measurably significant fall off on non-dosage days during the maintenance dosing. Although the number of cases is small, the 10-day loading regimen showed greater drug loading and retention compared with the 5 days loading regimen.

Antineoplastic Agents↗

PubMed2006

Motexafin-gadolinium taken up in vitro by at least 90% of glioblastoma cell nuclei.

PURPOSE: We present preclinical data showing the in vitro intranuclear uptake of motexafin gadolinium by glioblastoma multiforme cells, which could serve as a prelude to the future development of radiosensitizing techniques, such as gadolinium synchrotron stereotactic radiotherapy (GdSSR), a new putative treatment for glioblastoma multiforme. EXPERIMENTAL DESIGN: In this approach, administration of a tumor-seeking Gd-containing compound would be followed by stereotactic external beam radiotherapy with 51-keV photons from a synchrotron source. At least two criteria must be satisfied before this therapy can be established: Gd must accumulate in cancer cells and spare the normal tissue; Gd must be present in almost all the cancer cell nuclei. We address the in vitro intranuclear uptake of motexafin gadolinium in this article. We analyzed the Gd distribution with subcellular resolution in four human glioblastoma cell lines, using three independent methods: two novel synchrotron spectromicroscopic techniques and one confocal microscopy. We present in vitro evidence that the majority of the cell nuclei take up motexafin gadolinium, a drug that is known to selectively reach glioblastoma multiforme. RESULTS: With all three methods, we found Gd in at least 90% of the cell nuclei. The results are highly reproducible across different cell lines. The present data provide evidence for further studies, with the goal of developing GdSSR, a process that will require further in vivo animal and future clinical studies.

Brain Neoplasms↗

PubMed2005

Functional neuroimaging and electrophysiology biomarkers for clinical trials for cognition in schizophrenia.

"Measurement and Treatment Research to Improve Cognition in Schizophrenia" or MATRICS is a National Institute of Mental Health (NIMH)--sponsored research effort to drive novel drug development for the treatment of cognitive impairments in schizophrenia. On September 9-10, 2004, MATRICS convened representatives from NIMH, academia, and industry for the final of a series of consensus-oriented conferences, with this meeting entitled "New Approaches to Assessing and Improving Cognition in Schizophrenia." In this article, we present a summary of the discussions that focused on functional neuroimaging and electrophysiology biomarkers, outlining the research priorities, which included developing further consensus regarding the cognitive processes that are critical to examine in schizophrenia and the paradigms to examine them, resolving issues of test-retest reliability and discrepant findings in the literature, and additional basic research regarding the methods before fully implementing these paradigms in drug trials. Also summarized are the relative advantages and disadvantages of the different approaches and varying perspectives among the participants regarding these tools. Our hope is that this report will help guide and further stimulate coordinated efforts among researchers, industry, and funding agencies in meeting the urgent need for novel pharmacotherapeutics for cognitive impairments in schizophrenia and useful neurobiological indexes for tracking the resulting improvements in cognitive function.

Cognition Disorders↗

PubMed2005

Corollary discharge dysfunction in schizophrenia: can it explain auditory hallucinations?

Failure of corollary discharge, a mechanism for distinguishing self-generated from externally generated percepts, has been posited to underlie certain positive symptoms of schizophrenia, including auditory hallucinations. Although originally described in the visual system, corollary discharge may exist in the auditory system, whereby signals from motor speech commands prepare auditory cortex for self-generated speech. While associated with sensorimotor systems, it might also apply to inner speech or thought, regarded as our most complex motor act. In this paper, we describe the results of a series of studies in which we have shown that: (1) event-related brain potentials (ERPs) can be used to demonstrate the corollary discharge phenomenon during talking, (2) corollary discharge is abnormal in patients with schizophrenia, (3) EEG gamma band coherence between frontal and temporal lobes is greater during talking than listening and is disrupted by distorted feedback during talking in normals, and (4) patients with schizophrenia do not show this pattern for EEG gamma coherence. While these studies have identified ERPs and EEG gamma coherence indices of the efference copy/corollary discharge system and documented abnormalities in these systems in patients with schizophrenia, we have so far had limited success in establishing a relationship between these neurobiologic indicators of corollary discharge abnormality and reports of hallucinations in patients.

Auditory Cortex↗

PubMed2005

Delayed hemodynamic responses in schizophrenia.

While there are many reports of reduced amplitude of hemodynamic responses in schizophrenia, there are no reports of delayed hemodynamic responses, in spite of event-related brain potential (ERP) evidence of slowed neural responses. Recently, Henson et al. (2002) [Henson, R., Price, C., Rugg, M., Turner, R., Friston, K., 2002. Detecting latency differences in event-related BOLD responses: application to words versus nonwords and initial versus repeated face presentations. NeuroImage, 15:83-97] proposed a new method for testing small latency effects (<2 s) in hemodynamic responses. fMRI data were collected during a visual oddball task with infrequent (12%) targets (K) and frequent (88%) standards (X), presented every 1-3 s pseudorandomly, with 7-24 s between targets. SPM99 yielded parameter estimates for the hemodynamic response and its temporal derivative (TD). Beta images reflecting hemodynamic response magnitude to target stimuli were minimally thresholded (P < 0.05, uncorrected), and latencies were estimated for surviving voxels using TD and hemodynamic response beta values. DSM-IV schizophrenia patients (n = 12) and sex- and age-matched healthy control subjects (n = 12) were recruited from the community. Although groups differed only minimally in activation height, hemodynamic responses were significantly delayed in basal ganglia, thalamus, and anterior cingulate in patients with schizophrenia. Psychomotor slowing reflected in reaction times to targets recorded outside the magnet was related to hemodynamic slowing in basal ganglia, anterior cingulate, thalamus, as well as left cerebellum in controls. Delays in the hemodynamic response have far-reaching implications for understanding the pathophysiology of schizophrenia from slowed neural responses to slowed substrate delivery, and depending of the degree of delay, may raise methodological issues regarding modeling hemodynamic responses in patients and controls.

Adult↗

PubMed2005

Reduced gamma-band coherence to distorted feedback during speech when what you say is not what you hear.

BACKGROUND: Communication between the frontal lobes, where speech is generated, and the temporal lobes, where it is perceived, may occur through the action of an efference copy/corollary discharge mechanism that prepares the temporal lobes for the expected sound. We suggest that coherence of EEG in gamma-band between frontal and temporal lobes may reflect the successful action of such a mechanism. We tested the hypothesis that there would be a disruption of gamma-band coherence when the expected auditory consequence of speech does not match the auditory experience. METHOD: EEG was recorded from 21 healthy adult subjects as they uttered the sound [a:] (Talking condition) and as they heard these recorded sounds played back (Listening condition). As they spoke, subjects heard real-time feedback of the sounds that were: (1) pitch-shifted down one semi-tone, (2) pitch-shifted down one-half of a semi-tone, or (3) not pitch-shifted (veridical), each in separate runs. Event-related gamma coherence between frontal and temporal sites was calculated relative to the onset of the sound, as it was being spoken during Talking, and as it was being played back during Listening. RESULTS: Frontal-temporal gamma-band coherence spanning 33-43 Hz was greater during Talking than Listening and greater when speech was veridical than when it was distorted a whole semi-tone. CONCLUSIONS: Gamma-band fronto-temporal synchrony may reflect a "binding of expectation with experience." Disruption of this synchrony may provide feedback to the frontal lobes, particularly regions subserving vocalization, to implement sensorimotor adaptations to either adjust motor programs for speech production in the short run, or to reorganize expectations in the long run.

Adult↗

PubMed2005

Fine-tuning of auditory cortex during speech production.

The cortex suppresses sensory information when it is the result of a self-produced motor act, including the motor act of speaking. The specificity of the auditory cortical suppression to self-produced speech, a prediction derived from the posited operation of a precise forward model system, has not been established. We examined the auditory N100 component of the event-related brain potential elicited during speech production. While subjects uttered a vowel, they heard real-time feedback of their unaltered voice, their pitch-shifted voice, or an alien voice substituted for their own. The subjects' own unaltered voice feedback elicited a dampened auditory N100 response relative to the N100 elicited by altered or alien auditory feedback. This is consistent with the operation of a precise forward model modulating the auditory cortical response to self-generated speech and allowing immediate distinction of self and externally generated auditory stimuli.

Adult↗

PubMed2005

Population pharmacokinetics of motexafin gadolinium in adults with brain metastases or glioblastoma multiforme.

The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.

Adult↗

PubMed2004

Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging.

BACKGROUND: Schizophrenia is associated with deficits in using context to establish prepotent responses in complex paradigms and failures to inhibit prepotent responses once established. OBJECTIVE: To assess prepotent response establishment and inhibition in patients with schizophrenia using event-related brain potential (ERP) and functional magnetic resonance imaging (fMRI) in a simple NoGo task. To combine fMRI and ERP data to focus on fMRI activations associated with the brief (approximately 200 ms) moment of context updating reflected in the NoGo P300 ERP component. DESIGN AND SETTING: We collected ERP and fMRI data while subjects performed a NoGo task requiring a speedy button press to X stimuli (P=.88) but not to K stimuli (P=.12). The ERPs were collected at the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif; fMRIs were collected at Stanford University, Stanford, Calif. PARTICIPANTS: We recruited patients with DSM-IV schizophrenia (n=11) from the community and the VA hospital and sex- and age-matched healthy control subjects (n=11) from the community. MAIN OUTCOME MEASURES: Behavioral accuracy, P300 amplitudes and latencies, and fMRI activations suggested that patients with schizophrenia did not establish as strong a prepotent tendency to respond to the Go stimulus as healthy subjects. In healthy subjects, NoGo P300 was related to activations in the anterior cingulate cortex, dorsal lateral prefrontal cortex, and right inferior parietal lobule and caudate nucleus, perhaps reflecting conflict experienced when withholding a response, control needed to inhibit a response, and stopping a response in action, respectively. In patients with schizophrenia, NoGo P300 was modestly related to activations in the anterior cingulate cortex, which is consistent with experiencing conflict. CONCLUSIONS: The difference in ERP and fMRI responses to Go and NoGo stimuli suggested that inhibiting a response was easier for patients with schizophrenia than for healthy subjects. Correlations of P300 and fMRI data suggested that patients with schizophrenia and healthy subjects used different neural structures to inhibit responses, with healthy subjects using a more complex system.

Adult↗

PubMed2004

Electrophysiological evidence of corollary discharge dysfunction in schizophrenia during talking and thinking.

Failure of corollary discharge, a mechanism for distinguishing self-generated from externally-generated percepts, has been posited to underlie certain positive symptoms of schizophrenia, including auditory hallucinations. Although originally described in the visual system, corollary discharge may exist in the auditory system, whereby signals from motor speech commands prepare auditory cortex for self-generated speech. While associated with sensorimotor systems, it might also apply to inner speech or thought, regarded as our most complex motor act. We had four aims in the studies summarized in this paper: (1) to demonstrate the corollary discharge phenomenon during talking and inner speech in human volunteers using event-related brain potentials (ERPs), (2) to demonstrate that the corollary discharge is abnormal in patients with schizophrenia, (3) to demonstrate the role of frontal speech areas in the corollary discharge during talking, and (4) to relate the dysfunction of the corollary discharge in schizophrenia to auditory hallucinations. Using EEG and ERP measures, we addressed each aim in patients with schizophrenia (DSM IV) and healthy control subjects. The N1 component of the ERP reflected dampening of auditory cortex responsivity during talking and inner speech in control subjects but not in patients. EEG measures of coherence indicated inter-dependence of activity in the frontal speech production and temporal speech reception areas during talking in control subjects, but not in patients, especially those who hallucinated. These data suggest that a corollary discharge from frontal areas where thoughts are generated fails to alert auditory cortex that they are self-generated, leading to the misattribution of inner speech to external sources and producing the experience of auditory hallucinations.

Adult↗

PubMed2004

Selective attention in schizophrenia: sparing and loss of executive control.

OBJECTIVE: Auditory selective attention involves top-down modulation of sensory processing to selectively filter relevant from irrelevant information. Patients with schizophrenia have deficits in auditory selective attention, but whether these attention deficits are evident at the earliest stages of auditory processing or emerge later in the processing stream is unknown. METHOD: Event-related potentials were used to assess the integrity and time course of auditory attention in schizophrenia during a cross-modal selective attention task. A random sequence of equiprobable loud and soft speech sounds and bright and dim checkerboard patterns occurred every 800 to 1200 msec. A button press was required in response to soft speech sounds in the auditory attention task and to dim checkerboards in the visual attention task. Event-related potentials were recorded from 15 patients with DSM-IV schizophrenia and 16 age- and gender-matched healthy comparison subjects. RESULTS: As early as 50 msec, both patients and comparison subjects showed evidence of cross-modal selective attention. These attention effects were sustained until 300 msec in comparison subjects but were no longer evident in patients by 100 msec. CONCLUSIONS: Schizophrenia patients implemented an early attentional filter but failed to sustain selective attention later in the processing stream. This suggests that initially intact executive control of auditory attention cannot be sustained in schizophrenia, perhaps implicating dysfunction in frontotemporal pathways.

Acoustic Stimulation↗

PubMed2003

A black box at the end of the rainbow: searching for the perfect preconditioner.

Solution of large systems of linear algebraic equations is required in many areas of science and technology, and when several million unknown variables are involved, this apparently simple problem can assume gargantuan proportions. During the last half century many methods have been developed with the aim of providing reliable and cost-effective solutions to a wide range of system types. Many of these use 'pre-conditioners' to improve efficiency. The end-user, perhaps with limited knowledge of the mathematical basis, is presented with the task of choosing between a bewildering array of competing linear solvers and preconditioners. Here we survey currently available techniques and consider the feasibility of producing 'black-box' software capable of solving any linear system without further user input.

Journal Article↗

PubMed2003

Response-monitoring dysfunction in aging and Alzheimer's disease: an event-related potential study.

Executive control is a broad-reaching function that includes response monitoring and is likely implemented in the frontal lobes. Age- and dementia-related changes in response-monitoring were assessed during a Picture-Name Verification Task, using response-synchronized event-related potential (ERP) markers of response monitoring: the centrally oriented error-related negativity (ERN); the smaller and more frontally-oriented correct-response negativity (CRN); and the positivity associated with errors (Pe), a marker of error awareness. These were recorded from 10 younger and 10 older healthy controls, as well as 12 Alzheimer's disease (AD) patients. Although the older and younger controls showed equivalent accuracy, error awareness (Pe), and relative ERN>CRN amplitude, aging was associated with slower behavioral responses and decreased ERN amplitude. Although dementia was associated with decreased accuracy, decreased ERN, and a loss of relative ERN>CRN amplitude, error awareness (Pe) remained somewhat intact in AD patients. In AD patients, CRN amplitude was affected by item certainty (assessed a week earlier), being larger to items that were idiosyncratically difficult for patients to name.

Adult↗

PubMed2003

Anatomy of an error: ERP and fMRI.

Successful inhibition of pre-potent responses involves conflict; failed inhibition involves both conflict and errors, complicating the study of errors. Event-related potential (ERP) and functional magnetic resonance imaging (fMRI) data were collected while ten subjects (26-55 years old) performed a Go/NoGo task, with pre-potent responses (88% Go) and inhibition of responses (12% NoGo). We measured error-related negativity (ERN) to false alarms (FA), correct-related negativity (CRN) to hits, NoGo N2 to correct rejections (CR) and Go N2 to hits. ERP difference scores were derived (ERN-CRN; NoGoN2-GoN2) for correlating with fMRI contrasts (FA-hits; CR-hits). Age effects were removed from ERN and N2 difference scores, and conflict effects, reflected in N2 difference scores, were removed from ERN. The resulting ERN correlated with fMRI activations in both caudal and rostral anterior cingulate cortex (ACC), while N2 correlated with fMRI activations in caudal ACC and in executive control regions including dorsolateral prefrontal cortex. Thus, error and conflict monitoring may be dissociable, subserved by both overlapping and distinct ACC regions.

Adult↗

PubMed2003

Are impairments of action monitoring and executive control true dissociative dysfunctions in patients with schizophrenia?

OBJECTIVE: Impaired self-monitoring is considered a critical deficit of schizophrenia. The authors asked whether this is a specific and isolable impairment or is part of a global disturbance of cognitive and attentional functions. METHOD: Internal monitoring of erroneous actions, as well as three components of attentional control (conflict resolution, set switching, and preparatory attention) were assessed during performance of a single task by eight high-functioning patients with schizophrenia and eight comparison subjects. RESULTS: The patients exhibited no significant dysfunction of attentional control during task performance. In contrast, their ability to correct errors without external feedback and, by inference, to self-monitor their actions was markedly compromised. CONCLUSIONS: This finding suggests that dysfunction of self-monitoring in schizophrenia does not necessarily reflect a general decline in cognitive function but is evidence of disproportionately pronounced impairment of action monitoring, which may be mediated by a distinct subsystem within the brain's executive attention networks.

Adult↗

PubMed2002

Reduced communication between frontal and temporal lobes during talking in schizophrenia.

BACKGROUND: Communication between the frontal lobes, where speech and verbal thoughts are generated, and the temporal lobes, where they are perceived, may occur through the action of a corollary discharge. Its dysfunction may underlie failure to recognize inner speech as self-generated and account for auditory hallucinations in schizophrenia. METHODS: Electroencephalogram was recorded from 10 healthy adults and 12 patients with schizophrenia (DSM-IV) in two conditions: talking aloud and listening to their own played-back speech. Event-related electroencephalogram coherence to acoustic stimuli presented during both conditions was calculated between frontal and temporal pairs, for delta, theta, alpha, beta, and gamma frequency bands. RESULTS: Talking produced greater coherence than listening between frontal-temporal regions in all frequency bands; however, in the lower frequencies (delta and theta), there were significant interactions of group and condition. This finding revealed that patients failed to show an increase in coherence during talking, especially over the speech production and speech reception areas of the left hemisphere, and especially in patients prone to hallucinate. CONCLUSIONS: Reduced fronto-temporal functional connectivity may contribute to the misattribution of inner thoughts to external voices in schizophrenia.

Adult↗

PubMed2002

N400 and automatic semantic processing abnormalities in patients with schizophrenia.

BACKGROUND: One factor hypothesized to underlie thinking disturbance in patients with schizophrenia is abnormal or disinhibited automatic spreading activation of semantic networks, which can be assessed using the N400 event-related potential. N400 is a negative-going component elicited at about 400 milliseconds following semantic stimuli that are not primed by the preceding context. Semantic priming refers to facilitated semantic processing gained through preexposure to semantic context, which can happen automatically or strategically. Using N400, inferences can be drawn regarding the extent to which a given context primes a word. METHODS: During a picture-word matching task, N400s to primed (exact match) and unprimed (remotely related) words were recorded from 18 healthy control subjects and 18 patients with schizophrenia performing a picture-word matching task. A short interval (325 milliseconds) between picture and word onset (stimulus-onset asynchrony) was used to optimize the role of automatic spreading semantic activation and to minimize the role of attention, expectancy, preparation, and working memory. RESULTS: Despite behavioral evidence of normal semantic priming, patients generated an abnormally small N400 (ie, less negative) to unprimed words. The N400 to primed words was neither larger nor smaller in patients than in controls, suggesting normal use of context. CONCLUSIONS: A reduced N400 to unprimed words in patients with schizophrenia suggests that there was inappropriate priming of words by remotely related semantic contexts. This is consistent with an overly broad automatic spread of activation through semantic networks in patients with schizophrenia.

Adult↗

PubMed2002

Initial clinical results of stereotactic radiotherapy for the treatment of craniopharyngiomas.

The efficacy and toxicity of stereotactic radiotherapy (SRT) for the treatment of craniopharyngioma has been retrospectively evaluated in 16 patients. The median tumor diameter was 2.8 cm (range 1.5-6.1) and the median tumor volume was 7.7 cc (range 0.7-62.8). SRT was delivered to a single isocenter using a dedicated 6 MV linear accelerator to patients immobilized with a relocatable stereotactic head frame. The three-year actuarial overall survival was 93% and the rate of survival free of any imaging evidence of progressive disease was 75%. The three-year actuarial survival rates free of solid tumor growth or cyst enlargement were 94% and 81% respectively. Our results suggest that SRT is a safe and effective treatment approach for patients with craniopharyngioma. Long-term follow-up is required to determine whether the normal tissue-sparing inherent with SRT results in reduction of the neurocognitive effects of conventional radiotherapy for craniopharyngioma. SRT can be delivered to craniopharyngioma that may be difficult to treat with stereotactic radiosurgery due to proximity of the optic chiasm. Further clinical experience is necessary to determine the clinical utility of beam shaping in the setting of SRT.

Adolescent↗