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Transcranial magnetic stimulation
Depression has an annual prevalence of 1-6% in the community; 50-60% of depressed individuals might not respond to conventional pharmacotherapy. Transcranial magnetic stimulation (TMS) non-invasively stimulates superficial cortex in patients, for investigative and therapeutic purposes. It is usually applied over the prefrontal cortex at frequencies of 1-20 Hz at motor threshold intensity. We present a meta-analysis of 24 studies evaluating the antidepressant effect of TMS for major depressive or bipolar disorder in treatment groups ≥10 patients. Out of 617 patients receiving active rTMS, 218 (35.3%) were classified as 'responders', whereas only 71 (13.1%) of 543 patients undergoing sham rTMS met the criteria for clinical response. The Peto odds ratio meta-analysis indicated that this difference is statistically significant, with an odds ratio of 3.88 (95%-CI: 2.94-5.13). Heterogeneity between studies did not exceed that expected by chance and there was no significant publication bias. Based on these data, five patients (95% CI = 4-6) need to be treated in order to obtain a clinical response attributable to rTMS, a respectable effect size among psychiatric (add-on) treatments. Unfortunately, there is no compelling evidence regarding the most effective combination of rTMS parameters. The literature indicates that future trials should employ a greater number of rTMS sessions, adequate concealment allocation and an individualized approach to locating the DLPFC using neuroimaging. Also, more knowledge is needed regarding the characteristics of patients who benefit from this treatment and the size and persistence of clinical effects. © 2009 Elsevier Ltd. All rights reserved.
Meta-analysis of magnetic resonance imaging studies of the corpus callosum in schizophrenia
Objectives: The corpus callosum plays a pivotal role in inter-hemispheric transfer and integration of information. Magnetic resonance studies have reported callosal abnormalities in schizophrenia but findings have been inconsistent. Uncertainty has persisted despite a meta-analytic evaluation of this structure several years ago. We set out to perform a further meta-analysis with the addition of the numerous reports published on the subject to test the hypothesis that the corpus callosum is abnormal in schizophrenia. Method: A systematic search was carried out to identify suitable magnetic resonance studies which reported callosal areas in schizophrenia compared to controls. Results from the retrieved studies were compared in a meta-analysis whilst the influence of biological and clinical variables on effect size was ascertained with meta-regression analysis. Results: Twenty-eight studies were identified. Corpus callosum area was reduced in schizophrenia in comparison to healthy volunteers. This effect was larger in first episode patients. similarly, heterogeneity detected among the studies was associated with course of illness indicating that chronic subjects with schizophrenia showed larger callosal areas. There was no evidence of publication bias. CONCLUsIONs: This study confirms the presence of reduced callosal areas in schizophrenia. The effect is of a larger magnitude at first presentation and less so in subjects with a chronic course generally medicated with antipsychotics.
Transcranial magnetic stimulation
Depression is a common disorder with an annual prevalence that varies from 1% to 6% in the community. It is associated with a high rate of recurrence; up to 50-60% of depressed individuals may not respond to conventional pharmacotherapy. This reinforces the need to find alternative treatments to improve the outcome of such patients. Transcranial magnetic stimulation (TMS) allows for the non-invasive stimulation of superficial cortex in patients, both for investigative and therapeutic purposes. It is usually applied over the prefrontal cortex at frequencies of 1-20 Hz and at an intensity around motor threshold. A meta-analysis is presented, including 31 studies evaluating the antidepressant effect of TMS. Repetitive (r)TMS was more effective in the treatment of depression than sham rTMS, with a medium-sized effect. Studies that have examined rTMS efficacy in the treatment of depression are highly heterogeneous in terms of both sample characteristics and treatment parameters. Moreover, most of them have employed a relatively small number of participants. Strict double-blinding cannot be guaranteed due to flawed sham conditions. All of these factors have the potential to lead to errors in the results of the individual studies and may have affected the result of the present meta-analysis. Unfortunately, there is no compelling evidence regarding the most effective combination of rTMS parameters. The literature suggests that future trials should employ a greater number of rTMS sessions, adequate concealment allocation and an individualized approach to locating the DLPFC using neuroimaging. Until the optimal treatment parameters are delineated, rTMS remains an experimental approach for the treatment of depression. More knowledge regarding the characteristics of patients who benefit from this treatment and the size and persistence of clinical effects is needed. © 2006 Elsevier Ltd. All rights reserved.
Automatic classification of SPECT images of Alzheimer's disease patients and control subjects
In this article we study the use of SPECT perfusion imaging for the diagnosis of Alzheimer's disease. We present a classifier based approach that does not need any explicit knowledge about the pathology. We directly use the voxel intensities as features. This approach is compared with three classical approaches: regions of interests, statistical parametric mapping and visual analysis which is the most commonly used method. We tested our method both on simulated and on real data. The realistic simulations give us total control about the ground truth. On real data, our method was more sensitive than the human experts, while having an acceptable specificity. We conclude that an automatic method can be a useful help for clinicians. © Springer-Verlag Berlin Heidelberg 2004.
Effects of a single dose of the acetylcholinesterase inhibitor velnacrine on recognition memory and regional cerebral blood flow in Alzheimer's disease.
The effects of a single oral dose of the acetylcholinesterase inhibitor velnacrine maleate on word and object recognition memory and regional uptake of 99mTc-exametazime were examined in patients with Alzheimer's disease. Word recognition memory was marginally improved 2 h after 75 mg velnacrine. With the same dose of velnacrine a relative increase in superior frontal uptake of 99mTc-exametazime was shown with single photon emission computed tomography (SPECT). This suggests increased regional perfusion and metabolism as a consequence of cholinergic stimulation. The effect did not co-vary with the degree of memory improvement, but, instead, more cognitively impaired patients showed a greater increase in tracer uptake after velnacrine, suggesting cholinergic hypersensitivity in the brains of Alzheimer patients.
A comparison of Tc-99m HM-PAO and I-123 IMP cerebral SPECT images in Alzheimer's disease and multi-infarct dementia.
SPECT images of the brain can be obtained using either 123I labelled amines or 99mTc-hexamethylpropyleneamineoxime (HM-PAO). Both materials produce images which are blood flow dominated and so appear similar in normal subjects, although the respective mechanisms of uptake are not yet finally established. It seems likely, however, that the different mechanisms of uptake are responsible for recent reports of some differences seen in images obtained with the two types of agent in patients with cerebral pathology, mainly cerebrovascular disease. In this study, 12 demented patients, 6 with dementia of the Alzheimer type (DAT) and 6 with multi infarct dementia (MID), were imaged with 123I-isopropylamphetamine (IMP) and 99mTc-HM-PAO and the images compared. Significantly more lesions were seen with IMP than HM-PAO (P less than 0.02); out of a possible 120 sites, 41 lesions were seen with IMP compared to 28 with HM-PAO, 23 being seen with both agents. However, it is concluded that either agent can be used for the differential diagnosis of dementia, a task for which the new cerebral blood flow agents seem well suited.
A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease.
We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, (["diffusion tensor"] and ["Alzheimer*" or "mild cognitive impairment"]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.
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.
Neuropsychological function and diurnal variation in depression.
Twenty-six patients suffering from DSM-III-R major depressive episode with diurnal variation of mood were examined at approximately 8 AM and 8 PM, using a neuropsychological test battery. We found that tests of executive function, especially the verbal fluency test, were sensitive measures of diurnal variation, but that personality measures were relatively robust in that they were not significantly affected by diurnal variations of mood. The relevance of detecting and assessing diurnal changes of mood with reliable, objective measures of performance is discussed.
Cognitive brain potentials and regional cerebral blood flow equivalents during two- and three-sound auditory "oddball tasks".
Ten healthy volunteers were examined with single photon emission tomography and 99mTc-exametazime. They were studied on 2 occasions, during a 2- and a 3-sound auditory discrimination (oddball) task. Twenty healthy volunteers were used as controls, studied once at rest. During the 2-tone task there was a bilateral posterior (occipito-) temporal and medial frontal activation, a left pericentral increase, and posterior cingulate suppression. During the 3-sound task activation was again found in posterior (occipito-) temporal, medial frontal cortex, left pericentral, with a small non-significant reduction in posterior cingulate uptake. Compared with the 2-tone task, there was a trend towards higher activity in left medial frontal, right posterior temporal and posterior cingulate cortex in the 3-sound task. P3b amplitudes were negatively correlated with posterior cingulate tracer uptake during both tasks. Positive correlations with P3b amplitudes were found in various frontal and temporal regions. These results are consistent with more invasive localisation studies of P3b. Posterior cingulate cortex appears to be inhibited during the oddball tasks, the more so, the more restricted the range of stimuli, and the greater the task-related recruitment of neurones (P3b amplitude). As expected from its more frontal distribution, P3a amplitude was positively correlated with anterior cingulate tracer uptake, and negatively correlated with temporal cortical activity.
Diurnal variation of mood and neuropsychological function in major depression with melancholia.
20 DSM-III-R melancholics with clinically evident diurnal symptoms and 20 controls were assessed with a battery of neuropsychological tests, a test of maximum voluntary hand-grip, and neuroendocrine measures of hypothalamic-pituitary-adrenal axis function morning and evening in a 24-h period, using a balanced design. The morning pattern of neuropsychological impairment in the melancholics was comprehensive, affecting attention and concentration/working memory, episodic memory, reaction time and, strikingly, the speed of simultaneous match to sample, which was performed more slowly than the version of the task delayed to 0 or 4 s. The melancholics were significantly weaker than controls, on a measure of maximal voluntary contraction. Significantly improved neuropsychological function was seen in the melancholic patients in the evening, in line with diurnal improvement in mood; there was also a large increase in strength. Slowing on the digit symbol substitution test, the simultaneous match to sample task, total errors on the match to sample and hand-grip remained impaired in the evening compared to controls; other neuropsychological measures were no longer statistically different from control values which were often worsened. Neuroendocrine measures showed significantly raised levels of cortisol and ACTH morning and evening in the melancholics. Morning cortisol in the melancholics correlated with the diurnal improvement in neuropsychological functioning. The results have implications for the timing of neuropsychological assessment in major depression. Indices of neuropsychological and motor function may be as reliable quantitative estimates of illness severity as subjective estimates of mood.
State changes in brain activity shown by the uptake of 99mTc-exametazime with single photon emission tomography in major depression before and after treatment.
Twenty-eight patients with a major depressive episode previously investigated at rest using Single Photon Emission Tomography (SPET or SPECT) with 99mTc-exametazime, were followed up at an interval of 9-28 months with the same investigation after full recovery. All patients were unipolar and were rated on the Newcastle scale and with the 17-item Hamilton scale. The uptake of 99mTc-Exametazime was expressed relative to calcarine/occipital cortex. Sixteen patients were scanned when optimally matched for drug treatment (4) or on both occasions drug free (12). The other 12 patients were fully recovered but could not be matched for drug status; these patients showed significantly more retardation, diurnal mood variation and guilt at presentation. Significant bilateral increases in tracer uptake were confined to basal ganglia and inferior anterior cingulate cortex in the matched group, where there were additional increases in thalamus and posterior cingulate cortex on the right side. There were no statistically discernible changes in the neocortex in the matched sample. The unmatched sample yielded inconclusive evidence of increased tracer uptake in left temporal cortex. The findings give a potential focus to the neuropharmacological analysis of depressive illness because the topography of the state change in brain function implicates dopamine function.