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Possible structural abnormality of the brainstem in unipolar depressive illness: a transcranial ultrasound and diffusion tensor magnetic resonance imaging study.
BACKGROUND: Most empirically derived antidepressants increase monoamine levels. The nuclei of cells synthesising these monoamines are located in the brainstem, and projection tracts such as the medial forebrain bundle reach virtually all other brain areas. Two studies of unipolar depressive illness using transcranial ultrasound have reported reduced echogenicity of the brainstem midline in unipolar depressed patients. This may be consistent with disruption of white matter tracts, including the medial forebrain bundle, and it has been suggested that the effect of such disruption could be reversed by antidepressants. OBJECTIVE: To replicate these findings in a group of unipolar depressed patients and controls. METHODS: Fifteen unipolar depressed patients and 15 controls were studied using transcranial ultrasound imaging and diffusion tensor magnetic resonance imaging (DT-MRI). RESULTS: No difference in echogenicity of the brainstem midline of unipolar depressed patients was found. A possible trend (Cohen's d = 0.39) in the direction of previous studies was found. Although the echogenicity of the brainstem midline of the control group was found to be similar to previous reports, there was no reduction in the patient group. Additionally, no structural abnormality of the brainstem was identified using DT-MRI. CONCLUSIONS: While these data do not replicate the findings of previous studies reporting a significant reduction in the echogenicity of the brainstem midline in unipolar depressed patients, the ultrasound investigation indicated that there may be a trend in this direction. Given the importance of identifying the causes of depressive illness, it is important that other groups attempt similar studies.
Statistical parametric mapping of (99m)Tc-HMPAO-SPECT images for the diagnosis of Alzheimer's disease: normalizing to cerebellar tracer uptake.
BACKGROUND: For a quantitative comparison of images obtained during (99m)Tc-hexamethylpropylene amine oxime (HMPAO) single-photon emission computed tomography (SPECT), brain activity values are usually normalized to a reference region. In studies of Alzheimer-type dementia (ATD), the cerebellum is often used as a reference region, assuming that it is spared any major pathological involvement. Statistical parametric mapping (SPM) may enhance the evaluation of SPECT scans in ATD patients. However, current SPM software only allows scaling to average whole brain activity (i.e., global normalization). The aim of this study was to develop an easily applied, objective, and reproducible method for determining average cerebellar tracer uptake so that images can be scaled specifically to cerebellar activity prior to the performance of SPM analysis. We also investigated whether cerebellar normalization increases the sensitivity and specificity of SPM analysis of ATD patients compared with global normalization. METHODS: Image files were taken from a parallel study investigating the use of SPECT as a diagnostic tool for early onset of ATD. Two methods for determining cerebellar activity were developed: one manually, using templates, the other automated, using specified coordinates entered into a Matlab routine. Group comparison of ATD patients versus controls (= healthy volunteers and depressed patients) was performed on a voxel-by-voxel basis using SPM 96 on Windows 95. Receiver operator characteristics (ROC) were computed for 20 student raters examining patient and control scans with and without single-subject SPMs. RESULTS: The reduction of cerebral blood flow in the group of ATD patients appeared 1.7 times greater in spatial extent when the tracer uptake was normalized to cerebellum rather than to average whole brain activity. Computing the reverse contrast (reductions in the control group compared with ATD patients) produced clusters of significance in globally normalized images which were not manifest after normalizing to cerebellum. This is consistent with the notion that the cerebellum is spared in ATD. Analysis of the area under the ROC curve showed that cerebellar-normalized SPM produced significantly improved accuracy over perfusion scans alone. CONCLUSION: An easily applied, objective, reproducible method was developed for normalizing images to cerebellum prior to the performance of SPM analysis. Cerebellar normalization produced more extensive abnormalities in SPM analyses of ATD patients than global normalization. Furthermore, cerebellar normalization produced marginally more accurate diagnostic results in single-scan SPM analysis of ATD patients than did global normalization.
Clinical and psychometric correlates of dopamine D2 binding in depression.
BACKGROUND: Single photon emission tomography (SPET) with the dopamine D2/3 ligand 123I-IBZM gives a semi-quantitative estimate of dopamine binding. In depressed patients, we predicted evidence of reduced function, i.e. increased binding, particularly in more retarded patients. METHODS: Fifteen depressed patients with major depressive illness and 15 healthy, age- and sex- matched volunteerS were examined with a clinical and neuropsychological test battery and high resolution IBZM-SPET. Estimates for specific binding were computed by averaging striatum to whole slice or frontal uptake ratios over 8-10 scans acquired from 70 min after tracer injection. RESULTS: Using whole slice as reference, left striatal uptake ratios did not significantly differ for patients from controls. Right ratios were significantly higher in patients than controls (P = 0.03). There were significant correlations between IBZM binding in left and right striatum and measures of reaction time and verbal fluency. CONCLUSIONS: Increased IBZM binding in striatum probably reflects reduced dopamine function, whether due to reduced release of dopamine, or secondary up-regulation of receptors. The observed abnormalities may be trait or state related, an issue that needs to be addressed with longitudinal study designs. The possible role of medication as a confounding variable requires further exploration.
Temporal lobe abnormalities in dementia and depression: a study using high resolution single photon emission tomography and magnetic resonance imaging.
OBJECTIVES: Perfusion SPECT and MRI were used to test the hypothesis that late onset depression is associated with brain abnormalities. METHODS: Forty depressed patients (DSM-III-R major depressive episode, not demented at two year follow up) were recruited who were either drug free, or on a stable dose of antidepressants for at least three weeks, as well as 22 demented patients (DSM-IIIR and NINCDS/ADRDA criteria for probable Alzheimer's disease). Patients were imaged at rest with a high resolution single slice 12 detector head scanner (SME-Neuro 900) and the cerebral perfusion marker 99mTc-exametazime (HM-PAO). Temporal lobe templates were fitted with brains pitched by 20 degrees-30 degrees. A subgroup of 41 patients (22 depressed) were also scanned using a Siemens Magnetron 1.0 Tesla magnetic resonance imager, using a FLAIR imaging sequence for the assessment of white matter hyperintensities, and a Turbo FLASH sequence for the measurement of medial temporal lobe width. RESULTS: Demented patients showed reduced perfusion, particularly in the left temporoparietal cortex. In these regions of interest, patients with late onset depression tended to have perfusion values intermediate between patients with early onset depression and demented patients. Differences in changes in white matter between demented and early and late onset depressive patients did not reach conventional levels of significance. Temporal lobe width differed between demented and depressed patients, but not between early and late onset depressed patients. Perfusion and temporal lobe width were not associated, but reductions of perfusion were associated with periventricular white matter changes. Mini mental state examination scores were associated with temporal perfusion in demented patients and with changes in deep white matter in depressed patients. Finally, severity of depressive symptoms was associated with decreased perfusion in frontotemporal and basal ganglia regions of interest. CONCLUSION: A cumulative effect of duration of illness on regional cerebral perfusion could not be confirmed. Late onset depression may show more abnormalities of deep white matter and of left temporoparietal perfusion than early onset depression, but the underlying pathology remains to be established.
Alzheimer's disease in adults with Down's syndrome: the relationship between regional cerebral blood flow equivalents and dementia.
Twenty adult patients suffering from Down's syndrome (DS) were recruited from hospitals and the community, together with 14 age- and sex-matched controls of normal intelligence. Dementia was diagnosed in patients using a structured psychiatric and physical examination as well as a carer interview and case notes. All patients and controls were imaged using single photon emission computerized tomography with 99mTc-exametazime. Four patients were clinically demented and all of them showed regional cerebral blood flow (rCBF) changes commonly found in patients with Alzheimer's disease, namely bilateral temporo-parietal deficits. These changes were also observed in about half of the patients without clinical evidence of dementia, but in none of the healthy controls. Across the group of patients, temporo-parietal rCBF deficits were associated with evidence of deterioration, but not with advancing age.
Estimating pre-morbid intellectual ability in the Alcoholic Korsakoff syndrome.
The National Adult Reading Test (NART) is widely used in clinical and research settings to estimate pre-morbid intellectual levels. The validity of the NART in estimating premorbid ability in Alcoholic Korsakoff Syndrome (AKS) is examined in the present study. Twenty AKS subjects were compared with 40 healthy controls. The validity of the NART as a pre-morbid measure in AKS was examined using four methods. AKS subjects made more NART errors than controls, had lower NART predicted IQ than demographically predicted IQ, made more NART errors than predicted by demographic variables and demonstrated NART performance which correlated with degree of memory impairment. It is concluded that NART performance is detrimentally affected by the AKS and that estimating pre-morbid intellectual level in Korsakoff's psychosis using the NART may be invalid. Furthermore, it is postulated that the impaired ability to pronounce correctly irregular words in AKS may reflect a failure in cognitive 'error checking' which may represent a consequence of frontal lobe dysfunction.
The use of ECT and MST in treating depression.
Electroconvulsive therapy (ECT) has been used clinically since 1938. Its most common use is in the treatment of depression: first line treatment where rapid recovery is a priority, but more frequently as an effective treatment for patients who do not respond to pharmacological and psychological approaches. Whilst it is widely hailed as an effective treatment, concerns about its effect on cognition remain. The development of magnetic seizure therapy (MST) over the past decade has attempted to devise a therapy with comparable efficacy to ECT, but without the associated cognitive side effects. The rationale for this is that MST uses magnetic fields to induce seizures in the cortex, without electrical stimulation of brain structures involved with memory. MST has been used successfully in the treatment of depression, yet there is a dearth of literature in comparison with ECT. We present a systematic review of the literature on ECT (from 2009-2011) and MST (from 2001-2011).
Cognitive impairment and fMRI in major depression.
Cognitive impairment in depression may be one of the more practically important aspects of the illness, responsible for much of its morbidity. It also is at the heart of its psychopathology, may contribute to strategies of treatment, and may give us a more easily quantifiable measure of impaired function to correlate with brain activity. Functional magnetic resonance imaging (fMRI) is ideally suited to examine brain function in depression. It has the correct time window to repeatedly sample cognitive task performance; it does not require exposure to radioactive tracers and can therefore be repeated many times; it also can be linked with high resolution structural images acquired in the same imaging session that help identify the regions of activation and support the spatial transformation necessary to compare the scans of different subjects. fMRI has already produced a series of consistent results in depression, identifying increased activity of rostral anterior cingulate and other medial prefrontal structures during effortful tasks and on occasion also increased dorsolateral prefrontal activity, suggesting increased possibly compensatory activity to maintain task performance. Investigating the interplay between limbic (orbitomedial) and 'cognitive' dorsolateral structures clearly has the potential to clarify important illness mechanisms of depressive illness.
Global cognitive impairment should be taken into account in SPECT-neuropsychology correlations: the example of verbal memory in very mild Alzheimer's disease.
PURPOSE: To examine the impact of severity of global cognitive impairment on SPECT-neuropsychology correlations, we correlated a verbal memory test with brain perfusion in patients with very mild Alzheimer's disease (AD), taking into account the Mini-Mental State Examination (MMSE) score as an index of global cognitive impairment. METHODS: Twenty-nine outpatients (mean age 78.2+/-5.5 years) affected by very mild, probable AD underwent brain SPECT with 99mTc-ethylcysteinate dimer and a word list learning test. SPM99 was used for voxel-based correlation analysis after normalisation to mean cerebellar counts (height threshold: p<0.01). In a first analysis, only age and years of education were inserted as nuisance covariates, while in a second analysis the MMSE score was inserted as well. RESULTS: In the first analysis, two clusters of significant correlation were found in both hemispheres, mainly including regions of the right hemisphere, such as the inferior parietal lobule, the middle temporal gyrus and the posterior cingulate. Significant correlation in the left hemisphere was observed in the lingual lobule, the parietal precuneus and the posterior cingulate. After taking into consideration the MMSE, the largest cluster of correlation was found in the left hemisphere, including the parietal gyrus angularis, the posterior cingulate and the middle temporal gyrus. CONCLUSION: The wide differences observed between the correlations achieved with and without taking into account the MMSE score indicate that severity of global cognitive impairment should be considered when searching for brain perfusion-neuropsychology correlations. In the present case, this strategy resulted in correlations that more closely matched neuropsychological models of verbal memory deficit.
Altered cerebral perfusion measured by SPECT in relatives of patients with schizophrenia. Correlations with memory and P300.
BACKGROUND: Genetic studies in schizophrenia are hampered by the complex heterogeneous clinical phenotype. Biological variables identified as trait markers of risk could clarify the mode of inheritance, define clinical subgroups and provide clues about aetiology. AIMS: To use single photon emission computed tomography (SPECT) to compare brain perfusion maps in patients with schizophrenia (n = 19), their asymptomatic 'high-risk' relatives (n = 36) and control subjects (n = 34) and to examine the relationships between imaging, memory and P300 event-related potential. METHOD: SPECT, memory tests and P300 recording were carried out. RESULTS: In the patients with schizophrenia and their relatives, perfusion was reduced in left inferior prefrontal and anterior cingulate cortex and increased bilaterally in a subcortical region. Perfusion significantly correlated with verbal memory and P300 amplitude in left inferior prefrontal cortex and with P300 latency in anterior cingulate cortex. CONCLUSIONS: Medication- and symptom-free relatives had altered regional perfusion intermediate between subjects with schizophrenia and controls. Impaired perfusion, verbal memory and P300 appear to be related traits associated with an increased risk of illness.
Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled fluorodeoxyglucose and positron emission tomography.
BACKGROUND: Diagnostic classes (derived from CATEGO) can be correlated with regional brain metabolism in patients with major psychiatric disorders. METHOD: Seventeen patients with schizophrenia, 15 with mania, 10 with depression and 10 healthy Volunteers were examined with positron emission tomography (PET) and 18F-labelled fluorodeoxyglucose, as a marker for glucose metabolism. The number of possible comparisons of regions of interest was reduced by principal-components analysis, and differences in factor scores were determined between diagnostic groups. RESULTS: Four independent factors, representing distributed brain systems, emerged: an anterior-posterior (1), a left-right temporal (2), a temporofrontal (3), and a mediofrontal (4) system, of which (1), (2) and (3) were abnormal in schizophrenia, (1) and (2) in mania, and (1) in depression. CONCLUSIONS: Abnormal patterns of metabolism could be detected, in decreasing order, in schizophrenia, mania and depression. Some of these abnormalities are likely to be due to medication, but others will be associated with structural or functional abnormalities of the frontolimbic system in the diagnostic groups.
Uptake of 99mTc-exametazime shown by single photon emission computerized tomography in obsessive-compulsive disorder compared with major depression and normal controls.
Twelve patients with obsessive-compulsive disorder (OCD) were investigated at rest using single photon emission computerized tomography with 99mTc-exametazime. The uptake of 99mTc-exametazime was expressed relative to calcarine/occipital cortex. Patients were matched for drug treatment with 12 patients with a major depressive episode and the patient groups were compared with a control group. Significant bilateral decreases in tracer uptake were confined to basal ganglia in the OCD group. There was a paradoxical positive correlation between anxiety ratings and tracer uptake to basal ganglia in the OCD group. The findings confirm that the functional topography of OCD implicates altered function in the basal ganglia.
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.