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A meta-analysis of depression severity and cognitive function.
BACKGROUND: Studies examining the way in which cognitive impairment is associated with depression have produced inconsistent findings. Different severity of depressed mood across studies may account for such conflicting reports. However, inconsistent results have also been reported in relation to the specific association of depression severity with cognitive performance. METHODS: A meta-analysis was conducted to examine the relationship between severity of depression and cognitive function, using the correlation (Pearson's r) between depression severity scores and neuropsychological test performance. Individual meta-analyses were conducted for composite measures of cognitive functional domains (episodic memory, executive function, processing speed, semantic memory, and visuo-spatial memory). Analyses were also done across functional domains for timed and un-timed tests. RESULTS: Significant correlations between depression severity and cognitive performance were found in the domains of episodic memory, executive function, and processing speed, but not for semantic memory or visuo-spatial memory. For both timed and un-timed cognitive measures there were equally significant correlations with depression severity. LIMITATIONS: There were few studies meeting inclusion criteria in some cognitive domains, papers had to be excluded due to insufficient data reporting, and there are limitations associated with the cross-sectional design. CONCLUSIONS: The results suggest that previous inconsistent findings of the relationship between the severity of depression and cognitive function may be attributed to random variations and lack of power within studies.
Meta-analysis of magnetic resonance imaging studies in chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome).
OBJECTIVES: 22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial syndrome (VCFS) or DiGeorge Syndrome, is a genetic disorder due to a micro deletion on chromosome 22q11.2. VCFS is associated with abnormalities in brain structure and with an increased risk of psychiatric disorders, particularly schizophrenia. The aim of this review was to statistically summarize the structural imaging literature on VCFS which due to the relatively rarity of the disorder tends to consider small sample sizes. METHOD: A systematic review and meta-analysis of region of interest (ROI) studies comparing VCFS with healthy controls was carried out. Significant heterogeneity was explored using meta-regression. RESULTS: Subjects with VCFS were characterised by global brain volumetric reduction including several cortical regions, cerebellum and hippocampus. The area of the corpus callosum was increased. CONCLUSIONS: Many regions extensively studied in schizophrenia were not covered in the existing VCFS literature. However, the studies considered support volumetric abnormalities which may help explain why VCFS is associated with a greatly increased risk of psychosis and other psychiatric disorders.
SPECT imaging in dementia.
Single photon emission computed tomography (SPECT) is a non-invasive functional neuroimaging technique that can be used in the diagnosis of dementia. This review describes some of the SPECT radiotracers available for imaging dementia patients and discusses recommendations for the clinical use of this imaging technique.
The cognitive neuropsychology of depression in the elderly.
BACKGROUND: The cognitive impairment of older depressed patients with late- as opposed to early-onset illness may show important differences, in that patients with early onset may suffer predominantly from impaired episodic memory, and those with late onset mainly from reductions of executive function and processing speed. METHOD: We searched Medline and EMBASE as well as individual papers' reference lists for relevant publications, recording comparisons in neuropsychological test results between early-onset depression (EOD), late-onset depression (LOD) and healthy volunteers. Effect sizes are presented for cognitive domains, such as executive function, processing speed, episodic memory, semantic memory and mental state examination. RESULTS: Patients with LOD showed greater reductions in processing speed and executive function than patients with EOD and controls. Both patient groups showed reduced function in all domains, except mental state, compared with controls. CONCLUSION: Pronounced executive deficits are typical of the late-onset patients described in published studies, while episodic memory impairment is not specific to early-onset illness. Possible reasons and confounders are discussed.
Factors modifying the efficacy of transcranial magnetic stimulation in the treatment of depression: a review.
OBJECTIVE: So far no convincing answer has emerged to the question of whether transcranial magnetic stimulation (TMS) can make a clinically useful contribution to the treatment of depression. Here we examine whether multiple sensitivity analyses can highlight parameters that predict a favorable treatment response. DATA SOURCES: Medline, Embase, and the Cochrane database for controlled trials were searched for relevant randomized controlled trials using the expression (transcranial magnetic stimulation or TMS) and depression. STUDY SELECTION: Thirty-three studies were identified and included in the random-effects meta-analysis, and between 17 and 31 studies were included in the secondary analyses comparing outcome of studies with different parameters. DATA EXTRACTION: Study data were extracted with a standardized data sheet. A meta-analysis based on Cohen d effect size measure was done for all studies and various subsets. Regression analysis of effect sizes with study parameters was done in 24 studies. DATA SYNTHESIS: Active TMS treatment was more effective than sham, but variability was too great to take any single study design as paradigmatic. No significant predictors of study effect size were found. Mean effect sizes were reduced, although still significant, in studies with stimulation intensity below 90% of motor threshold and new medication starting within 7 days before to 7 days after start of TMS. CONCLUSIONS: The absence of significant outcome predictors in the presence of significant variability of outcome measures can be interpreted in 2 ways: either study sizes and numbers and designs are insufficient to afford the power necessary to detect such predictors or TMS has a nonspecific effect on depression that is not influenced by study parameters. Large-scale comparative trials are necessary to decide between these interpretations.
Repeatability of motor and working-memory tasks in healthy older volunteers: assessment at functional MR imaging.
PURPOSE: To prospectively determine the repeatability of functional magnetic resonance (MR) imaging brain activation tasks in a group of healthy older male volunteers. MATERIALS AND METHODS: Local research ethics committee approval and informed consent were obtained. Sixteen men with a mean age of 69 years +/- 3 (standard deviation) performed finger-tapping and N-back (number of screens back) working-memory tasks. Each subject underwent MR imaging three times in weekly intervals. Within-subject task repeatability was analyzed in terms of the number of voxels classified as activated (activation extent), the mean activation amplitude, and (for finger tapping) the center of the mass of the activated region. A repeatability index was calculated to compare test-retest repeatability between subjects and between functional MR imaging tasks. Within-session, between-session, and between-subject variability was assessed by using analysis of variance testing of activation amplitude and extent. RESULTS: Nine of the 16 subjects generated useful data at all three MR imaging-functional task sessions. At single-subject, single-session analysis, cortical activation was identified in most subjects and at most sessions. The centers of the masses of motor cortex activation were highly reproducible (within 3 mm). Patterns of activation were qualitatively repeatable, but there was substantial variability in the amplitudes and extents of activated regions. Within-session coefficients of variation (CVs) for left- versus right-hand and right- versus left-hand finger tapping were, respectively, 65% and 43% for activation amplitude and 75% and 121% for activation extent. The between-session CVs for activation amplitude were similar to the within-session values, whereas between-session CVs for activation extent were much greater than within-session values, up to 206%. CONCLUSION: The generally poor quantitative task repeatability highlights the need for further methodologic developments before much reliance can be placed on functional MR imaging results of single-session experiments.
5-(123)I-A-85380 binding to the α4β2-nicotinic receptor in mild cognitive impairment.
Treatments currently licensed for Alzheimer's dementia target cholinergic brain systems. In vivo nicotinic receptor binding may provide an early marker of illness and treatment suitability. In this pilot, we examined nine patients with amnestic mild cognitive impairment (MCI) and 10 age and education matched healthy volunteers with high resolution SPECT and the nicotinic receptor ligand 5-(123)I-A-85380. Uptake data were analysed using voxel-based techniques for group comparisons and regression analyses with cognitive impairment as covariates. MCI patients had discrete reductions in uptake in medial temporal cortex. Correlations with cognitive impairment were found in left temporo-parietal areas (Addenbrooke's Cognitive Examination) and bilateral temporo-limbic areas (Rey Auditory Verbal Learning Test), and right parahippocampal gyrus (Rey Complex Figure Test) within the patient group. In vivo nicotinic receptor binding appears to be sensitive to brain changes in MCI. Larger scale explorations of patients undergoing treatment will be necessary to evaluate its use in predicting or monitoring treatment response.
Meta-analysis of magnetic resonance imaging studies of the corpus callosum in bipolar disorder.
OBJECTIVE: The corpus callosum (CC) plays a pivotal role in inter-hemispheric transfer and integration of information and is a relatively understudied structure in bipolar disorder (BD). Magnetic resonance imaging (MRI) studies have reported callosal abnormalities in this condition but findings have been inconsistent. Structural changes affecting the CC may underlie functional abnormalities in BD and could contribute to, or explain the pathophysiology of, the condition. METHOD: A systematic review was carried out to identify, appraise and summarize MRI studies which compared callosal areas in BD with an unrelated control group. The findings were then synthesized using random effects meta-analysis. Consideration was given to a number of variables to explain heterogeneity. RESULTS: Five case-control studies were identified. Bipolar patients showed reduced callosal areas in comparison with healthy volunteers with no evidence of heterogeneity or publication bias. CONCLUSION: Findings from this study indicate that callosal areas are reduced in BD and suggest that a failure to integrate information across the hemispheres may contribute to the pathophysiology of the disorder. Further research is necessary to clarify the underlying cellular changes leading to these morphometric differences.
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.
Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia.
OBJECTIVE: The authors sought to determine the diagnostic accuracy of 99mTc-HMPAO-SPECT in discriminating between Alzheimer disease (AD) and other dementias. METHODS: Articles published between 1985 and 2002 were retrieved systematically from MEDLINE and EMBASE, cross-referencing with personal collections and 13 narrative reviews. Of 301 studies identified, 48 survived exclusion criteria and contained extractable data. Two authors independently assessed and graded the methodology of all included studies. Diagnostic comparison groups included vascular dementia (VD; 13 studies), fronto-temporal dementia (FTD; 7 studies), normal healthy volunteers (27 studies), and non-dementia patients (13 studies). Where statistically justified, groups were pooled in a metaanalysis; summary receiver operating curves were constructed; and heterogeneity across studies examined by regression of the diagnostic odds ratio. RESULTS: The pooled weighted sensitivity of 99mTc-HMPAO-SPECT in discriminating clinically defined AD from VD was 71.3%; its specificity was 75.9%. The pooled weighted sensitivity and specificity for AD versus FTD were 71.5% and 78.2%, respectively. Variation in outcome across studies was not found to be attributable to any single factor. CONCLUSION: Pathological verification studies suggest that clinical criteria may be more sensitive in detecting AD than brain SPECT (81% versus 74%). However, SPECT studies provide a higher specificity against other types of dementia than clinical criteria (91% versus 70%). SPECT may, therefore, be helpful in the differential diagnosis of AD. Clinical follow-up studies are urgently required to establish its predictive validity with regard to natural history and treatment response.
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.
Transcranial magnetic stimulation for schizophrenia.
This is the protocol for a review and there is no abstract. The objectives are as follows: To estimate the effects of TMS alone compared with sham TMS or with 'standard management' and any other comparison interventions in reducing psychotic symptoms associated with schizophrenia.
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.