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P300 and smooth eye pursuit: concordance of abnormalities and relation to clinical features in DSM-III schizophrenia.
Twenty-five DSM-III-diagnosed schizophrenics and 37 normal and age-matched controls were examined using an oddball paradigm for the generation of P300 and smooth eye-pursuit tasks. Results were compared between groups and related to clinical characteristics, including a family history of psychiatric illness. Group differences were found for P300 amplitudes, latencies and eye-tracking. A family history of psychiatric illness was associated with normal eye-tracking in patients. Small P300 amplitudes alone and in combination with long P300 latencies were associated with a family history in controls.
Other magnetic resonance imaging techniques.
Relatively new developments in MRI, such as functional MRI (fMRI), magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) are rapidly developing into imaging modalities that will become clinically available in the near future. They have in common that their signal is somewhat easier to interpret than structural MRI: fMRI mirrors excess cerebral blood flow, in many cases representing brain activity, MRS gives the average volume concentrations of specific chemical compounds, and DTI reflects "directedness" of micro-anatomical structures, of particular use in white matter where fiber bundle disruption can be detected with great sensitivity. While structural changes in MRI have been disappointing in giving a diagnosis of sufficient sensitivity and specificity, these newer methods hold out hope for elucidating pathological changes and differentiating patient groups more rigorously. This paper summarizes promising research results that will yet have to be translated into real life clinical studies in larger groups of patients (e.g. memory clinic patients). Where available, we have tried to summarize results comparing different types of dementia.
The APOE ɛ4 allele modulates brain white matter integrity in healthy adults.
The Apolipoprotein E (APOE) ɛ4 allele is the best-established genetic risk factor for sporadic Alzheimer's disease, and is also associated with structural gray matter and functional brain changes in healthy young, middle-aged and elderly subjects. Because APOE is implicated in brain mechanisms associated with white matter (WM) development and repair, we investigated the potential role played by the APOE polymorphism on WM structure in healthy younger (aged 20-35 years) and older (aged 50-78 years) adults using diffusion tensor imaging. General reduction of fractional anisotropy and increase in mean diffusivity values was found in carriers of the APOE ɛ4 allele relative to non-carriers. No significant interactions between genotype and age were observed, suggesting that differences in WM structure between APOE ɛ4-carriers and non-carriers do not undergo significant differential changes with age. This result was not explained by differences in brain morphology or cognitive measures. The APOE ɛ4 allele modulates brain WM structure before any clinical or neurophysiological expression of impending disease.
Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis.
BACKGROUND: Several magnetic resonance imaging (MRI) studies have identified structural abnormalities in association with bipolar disorder. The literature is, however, heterogeneous and there is remaining uncertainty about which brain areas are pivotal to the pathogenesis of the condition. AIMS: To identify, appraise and summarise volumetric MRI studies of brain regions comparing bipolar disorder with an unrelated control group and individuals with schizophrenia. METHOD: A systematic review and random-effects meta-analysis was carried out to identify key areas of structural abnormality in bipolar disorder and whether the pattern of affected areas separated bipolar disorder from schizophrenia. Significant heterogeneity was explored using meta-regression. RESULTS: Participants with bipolar disorder are characterised by whole brain and prefrontal lobe volume reductions, and also by increases in the volume of the globus pallidus and lateral ventricles. In comparison with schizophrenia, bipolar disorder is associated with smaller lateral ventricular volume and enlarged amygdala volume. Heterogeneity was widespread and could be partly explained by clinical variables and year of publication, but generally not by differences in image acquisition. CONCLUSIONS: There appear to be robust changes in brain volume in bipolar disorder compared with healthy volunteers, although most changes do not seem to be diagnostically specific. Age and duration of illness appear to be key issues in determining the magnitude of observed effect sizes.
Screening for mild cognitive impairment: a systematic review.
OBJECTIVE: Patients with mild cognitive impairment account for a significant number of referrals to old age psychiatry services and specialist memory clinics. The cognitive evaluation of such patients is commonly restricted to brief dementia screens, with no consideration to their suitability for assessing MCI. Here, we review the utility of such cognitive screens for MCI and provide an overview of validated instruments. METHODS: We identified papers published after Petersen and colleagues 1999 MCI criteria (Petersen et al., 1999) and examining face-to-face cognitive screening for MCI from publication databases using combinations of the search terms 'mild cognitive impairment' and 'cognitive screening'. We also combined the former search with the names of 39 screening tests recently identified in a relevant review (Cullen et al., 2007). RESULTS: Fifteen cognitive screening instruments were identified, 11 cover a restricted range of cognitive domains. High sensitivity and specificity for MCI relative to healthy controls were reported for two comprehensive and two noncomprehensive screening instruments, adequate test-retest and inter-rater reliability for only one of these. With the exception of three studies, sample sizes were universally small (i.e. n = 100), and prognostic values were reported for only two of the identified 15 screening measures. Sensitivities of the full domain measures were universally high, but information about their specificity against psychiatric and non-progressive neurological conditions and predictive validity is lacking. CONCLUSION: Several cognitive screening instruments afford the clinician the ability to detect MCI, early AD, and in some cases non-AD dementia, but they cannot currently be used to make reliable inferences about the course and eventual outcome of MCI.
Blunted response to feedback information in depressive illness.
Depressive illness is associated with sustained widespread cognitive deficits, in addition to repeated experience of distressing emotions. An accepted theory, which broadly accounts for features of the syndrome, and its delayed response to antidepressant medication, is lacking. One possibility, which has received considerable attention, is that depressive illness is associated with a specific underlying deficit: a blunted or impaired ability to respond to feedback information. Unlike healthy controls, if patients with a depressive illness commit an error, they can be at increased risk of committing a subsequent error, possibly due to a failure to adjust performance in order to reduce the risk of error. In some speeded tasks, performance adjustment in humans is reliably associated with trial-to-trial change in reaction times (RTs), such as 'post-error slowing'. Previous studies of abnormal response to feedback have not investigated RT change in any detail. We used a combination of quantitative modelling of RTs and fMRI in 15 patients and 14 matched controls to test the hypothesis that depressive illness was associated with a blunted behavioural and neural response to feedback information during a gambling task. The results supported the hypothesis. Controls responded to negative ('lose') feedback by an increase in RT and activation of the anterior cingulate, the extent of which correlated with RT change. Patients did not significantly increase their RTs, nor activate the anterior cingulate. Controls responded to positive ('win') feedback by a reduction in RT and activation of the ventral striatum, the extent of which correlated with RT change. Patients neither reduced their RT nor activated the ventral striatum. RT adjustment correlated with self-reported anhedonia for both patients and controls. This behavioural deficit, together with its associated pattern of abnormal neural activity, implies that the anterior midline cortical substrate for error correction, which includes projections from the monoamine systems, is dysfunctional in depressive illness. Many studies have reported abnormalities of the medial frontal cortex in depressive illness; however, the mechanism by which antidepressant medication acts via the monoamine systems remains elusive. Our results suggest a direct link between the core subjective symptom of anhedonia, replicated neuropsychological deficits, electrophysiological and imaging abnormalities, and hypothesized dysfunction of the error correction system.
Neural predictive error signal correlates with depressive illness severity in a game paradigm.
Considerable experimental evidence supports the existence of predictive error signals in various brain regions during associative learning in animals and humans. These regions include the prefrontal cortex, temporal lobe, cerebellum and monoamine systems. Various quantitative theories have been developed to describe behaviour during learning, including Rescorla-Wagner, Temporal Difference and Kalman filter models. These theories may also account for neural error signals. Reviews of imaging studies of depressive illness have consistently implicated the prefrontal and temporal lobes as having abnormal function, and sometimes structure, whilst the monoamine systems are directly influenced by antidepressant medication. It was hypothesised that such abnormalities may be associated with a dysfunction of associative learning that would be reflected by different predictive error signals in depressed patients when compared with healthy controls. This was tested with 30 subjects, 15 with a major depressive illness, using a gambling paradigm and fMRI. Consistent with the hypothesis, depressed patients differed from controls in having an increased error signal. Additionally, for some brain regions, the magnitude of the error signal correlated with Hamilton depression rating of illness severity. Structural equation modelling was used to investigate hypothesised change in effective connectivity between prespecified regions of interest in the limbic and paralimbic system. Again, differences were found that in some cases correlated with illness severity. These results are discussed in the context of quantitative theories of brain function, clinical features of depressive illness and treatments.
Neuroticism as a predictor of mood change: the effects of tryptophan depletion.
BACKGROUND: Acute tryptophan depletion (ATD) results in a transient lowering of mood in patients recovered from depression and in healthy volunteers with a family history of affective disorders. The personality trait of neuroticism is strongly associated with depression. AIMS: To assess whether neuroticism predicts mood change in response to ATD in healthy volunteers. METHOD: Healthy volunteers who scored at the top and bottom fifth percentiles of neuroticism scores (17 and 15 respectively) were selected. In a double-blind, crossover study they received a tryptophan-free or a control drink. Mood and cognition were assessed. RESULTS: Neuroticism did not predict the amount of mood change following ATD but did moderate performance on the verbal fluency test. A family history of affective disorder (n=5) predicted mood change but not cognitive function following ATD. CONCLUSIONS: Neuroticism moderates aspects of cognitive function, but in this study it was not strongly related with mood change via serotonin.
Stimulation of the noradrenergic system enhances and blockade reduces memory for emotional material in man.
BACKGROUND: It is clearly established that emotional events tend to be remembered particularly vividly. The neurobiological substrates of this phenomenon are poorly understood. Recently, the noradrenergic system has been implicated in that beta blockade has been shown to reduce significantly the delayed recall of emotional material with matched neutral material being unaffected. METHODS: In the present study, 36 healthy young adults were randomly allocated to receive either yohimbine, which stimulates central noradrenergic activity, metoprolol which blocks noradrenergic activity, or matched placebo. The three groups were well matched. All capsules were taken orally, prior to viewing a narrated 11 slide show described a boy being involved in an accident. RESULTS: Yohimbine significantly elevated, and metoprolol reduced mean heart rate during the slide show relative to placebo, thus confirming the efficacy of the pharmacological manipulation. One week later, in a surprise' test, memory for the slide show was tested. As predicted, yohimbine-treated subjects recalled significantly more and metoprolol subjects fewer slides relative to placebo. This result was confirmed via analysis of multiple-choice recognition memory scores. CONCLUSIONS: We conclude that stimulation of the noradrenergic system results in the enhancement and blockade in a reduction of recall and recognition of emotional material in man.
Laterality of visuo-spatial attention in acute and chronic schizophrenia, major depression and in healthy controls.
Previous studies have suggested that schizophrenia is characterized by an asymmetry of visuo-spatial attention, in particular that acute unmedicated schizophrenics demonstrate relative inattention to right hemispace, whereas chronically medicated patients demonstrate the opposite pattern. In the present study, 30 unmedicated schizophrenic patients, 32 chronically medicated schizophrenic patients, 30 patients suffering from major depression and 60 healthy controls were assessed using two measures of hemispatial attentional neglect, namely letter and star cancellation. The results demonstrated that the chronic schizophrenic group made more total omissions for star cancellation (in both right and left hemispace), but that there was no difference between the groups in terms of omission asymmetry for either letter or star cancellation.
Correlation of regional cerebral blood flow equivalents measured by single photon emission computerized tomography with P300 latency and eye movement abnormality in schizophrenia.
Single photon emission tomography with the intravenous blood flow marker 99mTc-exametazime was carried out in 14 acutely ill drug-free schizophrenic patients from whom P300 event-related potential, smooth eye pursuit eye tracking and verbal fluency were measured within a few days of scanning. Smooth pursuit eye movement abnormality correlated significantly with abnormal tracer uptake in superior pre-frontal cortex on the right and left and inferior pre-frontal cortex on the left. Abnormal eye movement was also associated with higher tracer uptake in left anterior cingulate and left posterior cingulate. P300 latency was significantly correlated with higher tracer uptake in left superior pre-frontal and left parietal regions. Verbal fluency performance was negatively correlated with tracer uptake in left frontal region. Eye tracking abnormality in schizophrenia is associated with bilateral frontal lobe disturbance and P300 latency increase with left-sided frontal and temporoparietal dysfunction. There was, however, a significant inverse relation between eye tracking abnormalities and abnormal perfusion in the left anterior cingulate region.
Effects of fluvoxamine treatment on cognitive functioning in the alcoholic Korsakoff syndrome.
Eight patients suffering from the alcoholic Korsakoff syndrome (AKS) were entered in a double-blind cross-over trial of fluvoxamine 200 mg per day for 4 weeks versus matched placebo for 4 weeks. At the end of each phase, patients were assessed using a detailed neuropsychological test battery. Verbal fluency performance was significantly impaired following fluvoxamine treatment. No significant differences emerged on any of the other cognitive test measures when fluvoxamine was compared with placebo. However, two of the patients developed a major depressive episode while receiving fluvoxamine.
PASAT performance and the pattern of uptake of 99mTc-exametazime in brain estimated with single photon emission tomography.
The effect of the paced auditory serial addition test (PASAT) on the regional uptake of 99mTc-exametazime was determined by single photon emission computed tomography. Twenty insulin-treated diabetic outpatients were scanned at rest and during the performance of the PASAT task using split-dose injection of tracer. When resting and activation scans were compared there were significant decreases in tracer uptake in the right anterior cingulate and left posterior cingulate areas during PASAT activation. The findings are compared with previous studies which had implicated the anterior cingulate area in the mechanisms of attention in humans and other animals. The potentially confounding role of anxiety during attentional tasks is discussed.
Proactive interference and the neuropsychology of schizophrenia.
Gray, Felden, Rawlins, Hemsley & Smith (1991) have proposed a theoretical model of the neuropsychology of schizophrenia. A major feature of this model is that it is a weakening of the influences of memories of previous input on current perception/learning which is basic to the phenomenon of acute schizophrenia. In the present study, proactive interference (PI) was used as a paradigm to test this hypothesis. PI occurs when new learning is diminished as a consequence of previously learned material. According to our reading of the Gray et al. (1991) model, acutely ill unmedicated patients with schizophrenia should demonstrate reduced PI relative to controls. Ten acutely ill unmedicated patients with schizophrenia, 20 patients suffering from major depressive disorder, and 20 healthy controls were assessed using a PI paradigm. No significant differences in PI emerged between the groups. The results do not support this specific feature of the neuropsychological model of acute schizophrenia proposed by Gray et al. (1991).
A quantitative method for the assessment of overall effects from a number of similar electrophysiological studies: description and application to event-related potentials in Parkinson's disease.
Eight comparisons of auditory event-related potentials in idiopathic parkinsonism with matched controls were analysed using meta-analytic methods. Overall, there was clear evidence that P2, N2, and P3 peak latencies are delayed in patients. Effect sizes for the difference between patient and control latencies of N2, and to a lesser extent P3, were greater in studies with more cognitively impaired patients. High frequency high pass filter settings were significantly associated with shorter mean P3 latencies in controls, but not patients, so that greater effect sizes tended to be associated with higher high pass cut-off frequencies. These results support the argument for using quantitative methods for the review of clinical psychophysiological studies.
Single photon emission tomography with 99mTc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum.
Forty patients with a major depressive episode were investigated at rest using Single Photon Emission Tomography (SPET or SPECT) with 99mTc-exametazime, an intravenous ligand taken into brain in proportion to regional cerebral blood flow, thereby providing an estimate of regional metabolism. All patients were unipolar and were rated on the Newcastle scale and with the 17-item Hamilton scale. They also completed a range of neuropsychological tests. They were compared with 20 control subjects matched for age, gender, premorbid intelligence and education. The uptake of 99mTc-exametazime was expressed for a range of anatomically defined regions of interest relative to calcarine/occipital cortex. The depressed group showed reduced uptake in the majority of cortical and sub-cortical regions examined, most significantly in temporal, inferior frontal and parietal areas. Unexpectedly, there was a strong positive association between uptake and scores on the Newcastle scale, especially in cingulate areas and frontal cortex. After removing the variance attributable to the Newcastle ratings, however, there emerged the expected negative association between Hamilton scores and anterior tracer uptake. The associations between neuropsychological impairment and regional brain uptake of tracer in part reflected the pattern seen with the Newcastle scale: for example, impairment of memory function correlated with higher uptake into posterior cingulate areas. We propose that depressive illness may be characterised by two processes. One leads to an overall reduction in anterior neocortical function, perhaps related to symptom severity. The other mechanism is manifest as relatively increased function, most notably within cingulate and frontal areas of the cerebral cortex in association with psychotic symptoms. The findings offer new understanding of the brain states underlying depressive illness and a potential focus to subsequent neuropharmacological analysis.
Unilateral voluntary hand movement and regional cerebral uptake of technetium-99m-exametazime in human control subjects.
The study examines the sensitivity of a region of interest approach to detect functional changes in brain metabolism with SPECT and split-dose 99mTc-exametazime by replicating a simple hand movement experiment previously carried out with PET. Regional uptake of 99mTc-exametazime was determined in 12 healthy controls before and during a thumb-digit opposition task. Analysis of regional uptake was carried out blind to the hand used in the opposition task and showed a significant unilateral activation effect in a pericentral region of interest with opposite results in left- and right-handed activation. The maximum contralateral increase in tracer uptake was 16% before and 26% after correction for back diffusion. This is in good agreement with previous results employing absolute cerebral blood flow determination with PET and confirms the usefulness of 99mTc-exametazime SPECT for the examination of functional metabolic changes.