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Biomedical subjects

Adrienne C Lahti

Publications and source records attributed to Adrienne C Lahti.

11 recordsLinked to original sources
PubMed2006

Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia.

We report on the correlations between whole brain rCBF and the positive and negative symptoms of schizophrenia in two cohorts of patients who were scanned while free of antipsychotic medication. We hypothesized that positive symptoms would correlate with rCBF in limbic and paralimbic regions, and that negative symptoms would correlate with rCBF in frontal and parietal regions. Both cohorts of patients with schizophrenia (Cohort 1: n=32; Cohort 2: n=23) were scanned using PET with H(2)(15)O while free of antipsychotic medication for an average of 21 and 15 days, respectively. Both groups were scanned during a resting state. Using SPM99, we conducted pixel by pixel linear regression analyses between BPRS scores and whole brain rCBF. As hypothesized, positive symptoms correlated with rCBF in the anterior cingulate cortex (ACC) in a positive direction and with the hippocampus/parahippocampus in a negative direction in both patient groups. When the positive symptoms were further divided into disorganization and hallucination/delusion scores, similar positive correlations with ACC and negative correlations with hippocampus rCBF were found. In both cohorts, the disorganization scores correlated positively with rCBF in Broca's area. As expected, negative symptoms correlated inversely with rCBF in frontal and parietal regions. This study provides evidence that limbic dysfunction may underlie the production of positive symptoms. It suggests that abnormal function of Broca's area may add a specific language-related dimension to positive symptoms. This study also provides further support for an independent neurobiological substrate of negative symptoms distinct from positive symptoms. The involvement of both frontal and parietal regions is implicated in the pathophysiology of negative symptoms.

Adolescent↗
PubMed2005

The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers.

RATIONALE: N-methyl-D: -aspartate (NMDA) glutamate receptor antagonists have been reported to induce schizophrenia-like symptoms in humans, including memory impairments. Although the NMDA receptor has been shown to impair memory acquisition by disrupting long-term potentiation (LTP), limited research has been done on studying the effects of NMDA antagonists on the post-LTP cascade of events implicated in consolidation as measured by administering the drug after the initial learning experience. OBJECTIVE: The purpose of this experiment was to examine the effect of ketamine on mental status and to identify NMDA antagonist-induced memory deficits by comparing the recall performance of items presented both immediately before and during ketamine infusion. METHODS: Thirteen normal controls received a 60-min infusion of ketamine in a randomized double-blind, cross-over design. Mental status was evaluated with the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale. The first 12-item word list was presented immediately before infusion, and two lists were subsequently presented during the infusion. Verbal memory performance was assessed by measuring the delayed cued recall of each list 30 min after its presentation. RESULTS: At the beginning, subjects experienced perceptual and reality distortion symptoms, followed later by mild subjective effects. Ketamine significantly reduced the delayed recall of words presented immediately before, but not during, drug infusion. Ketamine-induced decrements in verbal recall correlated significantly with plasma ketamine levels. CONCLUSION: This study characterizes the behavioral effects associated with ketamine and suggests that ketamine decreases verbal memory performance by interfering with early consolidation processes.

Adult↗
PubMed2005

Functional effects of single dose first- and second-generation antipsychotic administration in subjects with schizophrenia.

Using PET with (15)O water, we characterized the time course of functional brain changes following the acute administration of a first- and a second-generation antipsychotic. Volunteers with schizophrenia were scanned while drug-free (baseline) and after single dose administration of haloperidol (n=6) or olanzapine (n=6) during a time course adapted to their plasma kinetics. To obtain brain location information, we contrasted each post-drug scan to baseline-acquired scans. We plotted the regional cerebral blood flow (rCBF) extracted in these locations and calculated the kinetic characteristics of the curves. Further, we compared and contrasted the rCBF changes induced by the drugs over the first 4 h post-drug administration. Dorsal and ventral striatum, thalamus and anterior cingulate cortex were activated with haloperidol, while frontal, temporal and cerebellum regions evidenced reduced flow. With olanzapine, ventral striatum, anterior cingulate and temporal cortices evidenced increases, and thalamus and lingual cortex decreases, in rCBF. Both drugs activated the caudate nucleus. Haloperidol induced greater activation of the dorsal striatum than did olanzapine. These data reveal important differences in patterns of brain activation between the drugs. Differences in the involvement in basal ganglia parallel known differences between the drugs in the emergence of acute EPS upon emergency administration.

Adult↗
PubMed2005

Subtle effects of ketamine on memory when administered following stimulus presentation.

RATIONALE: N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., PCP, ketamine) have been shown to impair learning/memory. Well documented in animal models, only limited research in humans has been reported. Findings to date are similar to results of animal studies; however, antagonists are typically administered before the learning experience. This may be problematic as memory failure could be secondary to inattention induced by the psychotomimetic effects of these drugs and/or alterations in sensory processing which can degrade the quality of the stimulus, thereby affecting the accuracy of recall. OBJECTIVE: The objective of the study is to compare the effects of ketamine vs placebo on recall for words when administered after stimulus presentation. METHODS: In this double-blind crossover study, 24 normal controls were given bolus injections of ketamine (0.3 mg/kg) or placebo. Immediately prior to infusion, subjects were administered a verbal memory test. Delayed recall was measured 45 min postinfusion. Mental status changes were assessed using the Brief Psychiatric Rating Scale. RESULTS: Subjects experienced a significant increase in psychiatric symptoms that peaked at 20 min. Results indicate no differences between the drug and placebo conditions for the memory task. However, reminiscence (i.e., recall of previously unrecalled items with repeated testing) was significantly reduced following ketamine administration compared to placebo. CONCLUSIONS: Findings suggest that aspects of memory consolidation are affected by drugs that interfere with NMDA receptor function.

Acoustic Stimulation↗
PubMed2005

Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia.

Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n=13) and medicated volunteers with schizophrenia (n=10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.

Adult↗
PubMed2004

Parametric study of accuracy and response time in schizophrenic persons making visual or auditory discriminations.

The inability to modulate processing time in conjunction with varying difficulty levels may be a core component of schizophrenia's cognitive deficit. In this study we used a parametric design to demonstrate this group's inability to increase and decrease response times in association with varying levels of task demand during auditory and visual recognition tasks. Unlike participants with schizophrenia, healthy volunteers responded to increasing levels of difficulty and high error by robustly increasing their average response times. In the group with schizophrenia, the greater the correlation between a subject's Response-Time and error rate the better was the subject in his/her overall discrimination accuracy. The higher their correlations the better they performed across all levels of difficulty in both modalities. The schizophrenia group's tendency to process high and low error conditions with similar behavioral resources may reflect a relatively static, non-dynamic cognitive repertoire.

Adult↗
PubMed2004

Clozapine but not haloperidol Re-establishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex.

Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with (15)O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n=6) and normal volunteers (NVs) (n=12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1). Rest, (2). sensory motor control (SMC) task, and (3). decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n=5) and/or clozapine (n=5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol- and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidol-treated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

Acoustic Stimulation↗
PubMed2003

Functional effects of antipsychotic drugs: comparing clozapine with haloperidol.

BACKGROUND: Using positron emission tomography (PET) with (15)O water, we compared regional cerebral blood flow (rCBF) patterns induced by clozapine or haloperidol in individuals with schizophrenia. Based on the known clinical characteristics of each drug, we hypothesized that brain regions where the drugs show similar rCBF patterns are among those mediating their antipsychotic actions; whereas, regions where the drugs produce different rCBF patterns are among those mediating their different drug actions, namely, haloperidol's motor side effects or clozapine's unique therapeutic action. METHODS: Persons with schizophrenia were scanned using PET with (15)O water, first after withdrawal of all psychotropic medication (n = 6), then again after treatment with therapeutic doses of haloperidol (n = 5) or clozapine (n = 5). RESULTS: Both drugs increased rCBF in the ventral striatum and decreased rCBF in hippocampus and ventrolateral frontal cortex. The rCBF increase associated with haloperidol was greater than that with clozapine in the dorsal and ventral striatum; the rCBF increase with clozapine was greater than that with haloperidol in cortical regions, including anterior cingulate and dorsolateral frontal cortex. CONCLUSIONS: These data suggest that the rCBF increase in ventral striatum and/or the decrease in hippocampus and/or ventrolateral frontal cortex mediate a common component of antipsychotic action of these drugs. The increased rCBF in dorsal striatum by haloperidol could well be associated with its prominent motor side effects, whereas the increased rCBF in the anterior cingulate or dorsolateral frontal cortex may mediate the superior antipsychotic action of clozapine. The proposals based on these preliminary observations require further study.

Adult↗
PubMed2003

Evaluating glutamatergic transmission in schizophrenia.

Our findings with schizophrenia and the glutamate system have relied on the characterization of the clinical response of patients to ketamine and their functional brain imaging response (rCBF) to the drug. Prior to the human studies reported here, we had evaluated the region activation characteristics and pharmacology of PCP and its congener MK 801 in animals. What I will report in this paper has been individually reported elsewhere but brought together here in a new synthesis.

Animals↗
PubMed2002

Effects of ketamine on leading saccades during smooth-pursuit eye movements may implicate cerebellar dysfunction in schizophrenia.

OBJECTIVE: Ketamine has proved a useful probe in the study of schizophrenia. Recent studies have shown that ketamine causes abnormalities in eye tracking similar to those seen in patients with schizophrenia. The authors examined the effects of ketamine on leading saccadic eye movements, a specific component of the smooth-pursuit response shown to be abnormal in schizophrenia patients and their relatives. METHOD: Twelve normal healthy volunteers received a 0.1 mg/kg bolus injection of ketamine or placebo in double-blind fashion during a smooth-pursuit eye-movement task. The number of leading saccades and the ratios of leading saccades to smooth-pursuit response time and to total saccadic eye-movement time were measured. RESULTS: Ketamine significantly increased the number of leading saccades and increased the leading saccade ratios for more slowly moving targets. Similar nonsignificant effects were noted at higher target speeds. Ketamine-induced abnormalities were similar to those observed in relatives of schizophrenia patients under drug-free conditions. CONCLUSIONS: These results suggest that neurotransmission mediated by N-methyl-D-aspartate (NMDA) is involved in eye-tracking abnormalities. The generation of disruptive leading saccades during smooth pursuit is thought to be mediated by frontal-thalamic-cerebellar circuitry. Evidence that the locus of this and other ketamine-induced smooth-pursuit eye-movement deficits involves NMDA receptor functioning in the cerebellum is suggested.

Adult↗