Evidence of fronto-thalamic involvement in schizophrenia.
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Adolescent↗
Biomedical subjects
R S Kahn
Publications and source records attributed to R S Kahn.
The effects of a sub-anaesthetic dose of ketamine on human selective attention.
A growing number of studies demonstrate that antagonists of the N-methyl-D-aspartate (NMDA) receptors can induce a broad range of psychophysiological anomalies in healthy subjects similar to those observed in schizophrenia. In this study, the effect of a sub-anaesthetic dose of the non-competitive NMDA antagonist, ketamine, on human selective attention was explored. It was hypothesized that ketamine would induce in healthy subjects psychophysiological anomalies that are commonly observed in schizophrenic patients, such as reduced P300 amplitude and a reduction of both mismatch negativity (MMN) and processing negativity (PN). In a double-blind randomized placebo-controlled design, healthy male volunteers (n = 18) were challenged with a sub-anaesthetic dose of ketamine (0.3 mg/kg i.v.) after which they were tested in a selective attention task. In this task, two types of stimuli were evenly presented to the left or right ear: standard tones (80%) and deviant tones (20%) of either 1000 or 1100 Hz. The duration of a stimulus (95 dB) was 50 ms, the interstimulus intervals were randomized between 1750 and 2150 ms. The volunteer was instructed to push a button as quickly as possible after hearing the deviant tone in a specified ear. Ketamine did not alter performance of the subjects: in both the placebo and drug condition their reaction times for and percentages of hits and false alarms did not differ. Ketamine did, however, reduce PN and the P300 amplitude (both in general and to deviant stimuli in particular). However, no drug effect on MMN was found. In addition, ketamine enhanced the N100 amplitude to deviant stimuli. In conclusion, ketamine induces some of the attentional deficits in healthy controls that are observed in schizophrenic patients. Consequently, reduced glutamatergic activity in the brain may be involved in some of the symptoms of schizophrenia.
Adult↗
Multivariate genetic analysis of brain structure in an extended twin design.
The hunt for genes influencing behavior may be aided by the study of intermediate phenotypes for several reasons. First, intermediate phenotypes may be influenced by only a few genes, which facilitates their detection. Second, many intermediate phenotypes can be measured on a continuous quantitative scale and thus can be assessed in affected and unaffected individuals. Continuous measures increase the statistical power to detect genetic effects (Neale et al., 1994), and allow studies to be designed to collect data from informative subjects such as extreme concordant or discordant pairs. Intermediate phenotypes for discrete traits, such as psychiatric disorders, can be neurotransmitter levels, brain function, or structure. In this paper we conduct a multivariate analysis of data from 111 twin pairs and 34 additional siblings on cerebellar volume, intracranial space, and body height. The analysis is carried out on the raw data and specifies a model for the mean and the covariance structure. Results suggest that cerebellar volume and intracranial space vary with age and sex. Brain volumes tend to decrease slightly with age, and males generally have a larger brain volume than females. The remaining phenotypic variance of cerebellar volume is largely genetic (88%). These genetic factors partly overlap with the genetic factors that explain variance in intracranial space and body height. The applied method is presented as a general approach for the analysis of intermediate phenotypes in which the effects of correlated variables on the observed scores are modeled through multivariate analysis.
Adult↗
Relapse prevention in major depressive disorder after successful ECT: a literature review and a naturalistic case series.
OBJECTIVE: Medication-resistance in major depressive disorder (MDD) may be related to high relapse rates after successful ECT when continued medication (C-MED) is used to prevent relapse. An alternative could be to continue ECT (C-ECT). METHOD: Patients with medication-resistant MDD responding to ECT were offered C-ECT without medication. Follow-up was 6 months. Publications from a literature search were screened against prespecified criteria. RESULTS: With C-ECT the 6-month relapse-rate was 50% (6/12, 95% CI:21-79) in our medication-resistant group. In the review we found with C-ECT 29% (7/24,CI:13-51) in 'unknown' medication resistance and no data about medication-resistant depression. With C-MED at 6 months: no data were found concerning medication-resistant depression, 28% (35/124,CI:20-36) in 'unknown' resistance and 13% (2/15,CI:2-41) in non-resistance. With C-MED at 12 months, 73% (16/22,CI:50-90), 50% (16/32,CI:32-68) and 27% (8/30,CI:12-46) were found, respectively. CONCLUSION: The efficacy of C-MED is related negatively to medication resistance before ECT. This may also be the case for C-ECT. Further studies with C-ECT are urgently needed.
Adult↗
Structural brain abnormalities in patients with schizophrenia and their healthy siblings.
OBJECTIVE: The authors sought to investigate the contribution of genotype on structural brain abnormalities in schizophrenia. METHOD: Intracranial volumes and volumes of the cerebrum, white and gray matter, lateral and third ventricles, frontal lobes, caudate nucleus, amygdala, hippocampus, parahippocampal gyrus, and the cerebellum were measured in 32 same-sex siblings discordant for schizophrenia and 32 matched comparison subjects by means of magnetic resonance imaging. RESULTS: Third ventricle volumes did not differ between the schizophrenic patients and their healthy siblings. However, both had higher third ventricle volumes than did the comparison subjects. The schizophrenic patients had lower cerebrum volumes than did the comparison subjects, whereas the cerebrum volume of the healthy siblings did not significantly differ from the patients or comparison subjects. Additionally, patients with schizophrenia displayed a volume reduction of the frontal lobe gray matter and a volume increase of the caudate nuclei and lateral ventricles compared to both their healthy siblings and comparison subjects. Intracranial volume, CSF volume, or volumes of the cerebellum, amygdala, hippocampus, or the parahippocampal gyrus did not significantly differ among the patients, siblings, and comparison subjects. CONCLUSIONS: Healthy siblings share third ventricle enlargement with their affected relatives and may partially display a reduction in cerebral volume. These findings suggest that third ventricular enlargement, and to some extent cerebral volume decrease, may be related to genetic defects that produce a susceptibility to schizophrenia.
Adult↗
Prenatal exposure to famine and brain morphology in schizophrenia.
OBJECTIVE: The authors assessed the effects of nutritional deficiency during the first trimester of pregnancy on brain morphology in patients with schizophrenia. METHOD: Nine schizophrenic patients and nine healthy comparison subjects exposed during the first trimester of gestation to the Dutch Hunger Winter were evaluated with magnetic resonance brain imaging, as were nine schizophrenic patients and nine healthy subjects who were not prenatally exposed to the famine. RESULTS: Prenatal famine exposure in patients with schizophrenia was associated with decreased intracranial volume. Prenatal Hunger Winter exposure alone was related to an increase in brain abnormalities, predominantly white matter hyperintensities. CONCLUSIONS: Nutritional deficiency during the first trimester of gestation resulted in an increase in clinical brain abnormalities and was associated with aberrant early brain development in patients with schizophrenia. Stunted brain development secondary to factors that affect brain growth during the first trimester of gestation may thus be a potential risk factor for developing schizophrenia.
Brain↗
Perception, mental imagery and reality discrimination in hallucinating and non-hallucinating schizophrenic patients.
OBJECTIVES: In this study the hypothesis was tested that hallucinations result from confusing external and internal stimulus sources, i.e., perception and imagery, respectively. DESIGN AND METHODS: Thirteen hallucinating and 19 non-hallucinating schizophrenic patients, as well as 14 control participants performed multiple tests of perception, vividness of mental imagery and the ability to discriminate between them (reality discrimination). These functions were tested in both the auditory and the visual modalities. RESULTS: There were no group differences on perceptual acuity. The results on one imagery task indicated that for the hallucinating patients, the relative, but not the absolute, level of vividness of mental images might be higher in the auditory modality, which was the modality in which 12 of the patients also experienced hallucinations, than in the visual modality. Finally, there was a positive relationship between severity of (auditory) hallucinations and reality discrimination problems. CONCLUSIONS: Hallucinations may result from increased vividness of mental imagery, and their severity increases with larger impairments in reality discrimination. It is recommended that research into, and cognitive behavioural therapy for, hallucinations should also focus on their sensory qualities.
Adult↗
Cerebral mirror-imaging in a monozygotic twin.
A healthy monozygotic twin of discordant handedness was scanned with functional magnetic resonance imaging during a language and a mental rotation task. Mirror-imaging was found for both cerebral functions.
Brain Mapping↗
Acute dystonia induced by drug treatment.
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Acute Disease↗
Prenatal exposure to the 1957 influenza pandemic and non-affective psychosis in The Netherlands.
Second-trimester exposure to the 1957 A2 influenza pandemic is a controversial risk factor for schizophrenia. Two earlier studies of the Dutch psychiatric registry failed to find an increased risk for exposed subjects, but diagnostic misclassification within the spectrum of non-affective psychoses has not yet been ruled out as an explanation for the negative findings. Using an enlarged data-set we examined not only whether second-trimester exposure to the epidemic is associated with an increased risk of schizophrenia (ICD:295), but also whether it is associated with an increased risk of paranoid states (ICD:297) or other non-organic psychoses (ICD:298). In this retrospective cohort study the risks of the above-mentioned disorders were compared for those exposed and unexposed to A2 influenza during the second trimester of fetal life. The risks for the exposed subjects were not significantly higher than the risks for the unexposed. The power of the study to detect a significant increase in the risk of schizophrenia was sufficient. If the relative risk of a lifetime hospitalization for schizophrenia for second-trimester exposed subjects (born January-April 1958) is assumed to be 1.3, the power of the study would be 0.97 (alpha=0.05; one-tailed testing). If the relative risk for subjects born five months after the peak of the epidemic (mid-February to mid-March 1958) is assumed to be 1.88, as reported for England and Wales, the power of the study would be close to 1.00. This was the largest study of its kind in Europe: 275 subjects were born in the period January-April 1958 and had a lifetime hospitalization for schizophrenia. This study indicates that there is no relation between second-trimester exposure to the 1957 influenza pandemic and risk of non-affective psychosis in the Dutch population. It adds to a growing body of work which does not support an association between maternal influenza and schizophrenia.
Adolescent↗
Volumetric analysis of frontal lobe regions in schizophrenia: relation to cognitive function and symptomatology.
BACKGROUND: The purpose of this study was to examine the structure of dorsolateral, medial, and orbital regions of the frontal lobe in schizophrenia, and to determine whether their volumetric measurements were related to cognitive function and symptomatology. METHODS: High resolution magnetic resonance imaging scans of the brains of 14 schizophrenic patients and 14 closely matched healthy controls were acquired. Volumes of gray and white matter of the left and right dorsolateral, medial, and orbital prefrontal brain regions were measured. Tests of verbal and visual memory and executive functions were used to assess cognitive function. The SANS and SAPS were used to obtain symptom ratings in patients. RESULTS: Data of 13 schizophrenic patients were analyzed. Patients showed a general, though not significant, decrease in volumes of frontal regions as compared to controls. In patients, but not in controls, smaller left and right prefrontal gray matter volumes were significantly correlated with impaired performance on immediate recall in verbal and visual memory and semantic fluency. Furthermore, in patients, smaller total orbitofrontal gray matter volume was significantly correlated with more severe negative symptomatology (rs = -.76, p = .006). CONCLUSIONS: These findings suggest that in schizophrenia, deficits in verbal and visual memory and semantic fluency and negative symptoms may be related to (subtle) abnormalities in frontal lobe structure.
Adolescent↗
P50 suppression and prepulse inhibition of the startle reflex in humans: a correlational study.
BACKGROUND: Sensory gating is an important feature of the normally functioning brain. When not operating correctly, it can contribute to different kinds of psychiatric illnesses by flooding the higher brain functions with useless information. Over the years, two paradigms have evolved to quantify the amount of sensory gating: the prepulse inhibition (PPI) of the startle reflex and the suppression of the P50 evoked potential. To enable comparison across studies it is important to find out to what extent these paradigms reflect the same processes. In the present study, this relationship was explored. METHODS: Thirty-one healthy male volunteers with no personal or family history of mental illness were tested on their ability to suppress the P50 wave and to inhibit the startle reflex. RESULTS: A significant positive correlation was found between PPI and P50 suppression mainly early in testing, when habituation of the startle reflex is taking place. Furthermore, a significant negative correlation was found between P50 suppression in the second half of testing and the habituation of the startle reflex. CONCLUSIONS: PPI and P50 suppression are correlated at an early stage of testing, when the process of habituation of the startle reflex is active. The role of the habituation in the correlation between these two measures needs to be further explored.
Acoustic Stimulation↗
Psychotic illness after prenatal exposure to the 1953 Dutch Flood Disaster.
We tested the hypothesis that maternal stress during pregnancy increases the risk of non-affective psychosis for the child. The concept of non-affective psychosis includes the ICD categories schizophrenic disorder, paranoid state and other non-organic psychosis. Data from the Dutch Psychiatric Registry were examined for an effect of the Flood Disaster of 1 February 1953. On this day, a gale caused a flood in the South-west of The Netherlands and 1835 people perished. Our study concerned the 19 villages where mortality exceeded 0.25%. The risk of non-affective psychosis for the cohort born in the period February-October 1953 was compared to the risks for the cohorts born in the corresponding periods of the previous and subsequent 2 years. The relative risk of non-affective psychosis for those exposed during gestation was 1.8 [95% Confidence Interval (CI): 0.9-3.5]. Thus, our study failed to demonstrate a significant association between prenatal exposure to maternal stress and risk of non-affective psychosis. The possible explanations for this finding are discussed.
Cohort Studies↗
D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study.
A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia.
Adult↗
Outcome of schizophrenia in relation to brain abnormalities.
This article reviews the 21 studies that investigated possible relationships between structural brain abnormalities and outcome in schizophrenia. Fifteen studies used computer tomography to visualize brain morphology. In these studies, images were obtained of the ventricles but not of specific brain regions. The remaining six studies used magnetic resonance imaging, examining possible relationships between outcome, ventricular size, and specific brain regions. One out of two studies found relationships between brain structure and outcome. The data suggest that the extent of ventricular enlargement in patients with schizophrenia may be related to outcome. No clear relationship between outcome and changes in specific brain regions was found. Apart from considerations about the methodology of measuring different brain regions, the procedure used to measure outcome is important. Outcome, as it is assessed at various points during the course of illness, may be variable and seems to fluctuate during the first 10 to 15 years of disease. Significantly, to date no studies relating outcome to brain structure have used patient samples with a duration of illness longer than 15 years.
Adult↗
Tardive dystonia.
This paper provides an overview of the phenomenology, epidemiology, and treatment of tardive dystonia. Tardive dystonia is one of the extrapyramidal syndromes that starts after long-term use of dopamine receptor antagonists. The diagnosis is based on the presence of chronic dystonia, defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Furthermore, dystonia must develop either during or within 3 months of a course of antipsychotic treatment, and other causes such as Wilson's disease, acute dystonia, or a conversion reaction must be ruled out. Tardive dystonia occurs in about 3 percent of patients on long-term antipsychotic treatment. Some probable risk factors for tardive dystonia are younger age, male, and the presence of tardive dyskinesia. The treatment of tardive dystonia starts with an evaluation of the need for using the causative drug. If antipsychotics must be continued, a switch to an atypical antipsychotic, particularly clozapine, may be helpful. If the dystonia is relatively localized, botulinum toxin is an effective but not well-known treatment possibility. If tardive dystonia is more extensive, either dopamine-depleting drugs or high dosages of anticholinergics can be tried.
Adult↗
Mood improvement from transcranial magnetic stimulation.
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Adult↗
Memory impairment in schizophrenia: a meta-analysis.
OBJECTIVE: Memory impairment is well documented in schizophrenia. Less is known, however, about the exact magnitude, pattern, and extent of the impairment. The effect of potential moderator variables, such as medication status and duration of illness, is also unclear. In this article, the authors presented meta-analyses of the published literature on recall and recognition memory performance between patients with schizophrenia and normal comparison subjects. METHOD: Meta-analyses were conducted on 70 studies that reported measures of long-term memory (free recall, cued recall, and recognition of verbal and nonverbal material) and short-term memory (digit span). Tests of categorical models were used in analyses of potential moderators (clinical variables and study characteristics). RESULTS: The findings revealed a significant and stable association between schizophrenia and memory impairment. The composite effect size for recall performance was large. Recognition showed less, but still significant, impairment. The magnitude of memory impairment was not affected by age, medication, duration of illness, patient status, severity of psychopathology, or positive symptoms. Negative symptoms showed a small but significant relation with memory impairment. CONCLUSIONS: This meta-analysis documented significant memory impairment in schizophrenia. The impairment was stable, wide ranging, and not substantially affected by potential moderating factors such as severity of psychopathology and duration of illness.
Comorbidity↗