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Transcranial stimulation in depression.
Transcranial direct current stimulation is coming of age with the large treatment study published in this issue. We review transcranial stimulation methods, their efficacy and the likely impact on National Health Service (NHS) practice. Their use in individuals who do not respond to or cannot tolerate medication should now be explored in large controlled naturalistic studies in the NHS.
Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses.
Previous meta-analyses of structural MRI studies have shown diffuse cortical and sub-cortical abnormalities in unipolar depression. However, the presence of duplicate publications, recruitment of particular age groups and the selection of specific regions of interest means that there is uncertainty about the balance of current research. Moreover, the lack of systematic exploration of highly significant heterogeneity has prevented the generalisability of finding. A systematic review and random-effects meta-analysis was carried out to estimate effect sizes. Possible publication bias, and the impact of various study design characteristics on the magnitude of the observed effect size were systematically explored. The aim of this study was 1) to include structural MRI studies systematically comparing unipolar depression with bipolar disorder and healthy volunteers; 2) to consider all available structures of interest without specific age limits, avoiding data duplication, and 3) to explore the influence of factors contributing to the measured effect sizes systematically with meta-regression analyses. Unipolar depression was characterised by reduced brain volume in areas involved in emotional processing, including the frontal cortex, orbitofrontal cortex, cingulate cortex, hippocampus and striatum. There was also evidence of pituitary enlargement and an excess of white matter hyperintensity volume in unipolar depression. Factors which influenced the magnitude of the observed effect sizes were differences in methods, clinical variables, pharmacological interventions and sample age.
Tackling dementia in patients with Parkinson's disease.
Dementia more than one year after the onset of motor features associated with Parkinson's disease is defined as Parkinson's disease with dementia (PDD). If it develops within one year of the motor features, the term dementia with Lewy bodies (DLB) is used. Since clinical and pathological features are similar, it is generally accepted that both represent a continuum of the same disorder. PDD together with DLB account for around one fifth of all cases of dementia in the elderly. Studies suggest that most patients with Parkinson's disease would eventually develop dementia if they lived long enough. The diagnosis of PDD in the presence of long-standing pronounced motor features rarely poses a diagnostic dilemma. However, the diagnosis of DLB may be more difficult. It relies on the revised consensus clinical criteria which require the presence of at least two of the following three syndromes: persistent visual hallucinations, fluctuating defects in cognitive and functional ability, and parkinsonism. An early referral to a specialist clinic may not only help to confirm the diagnosis, but also to co-ordinate the group of professionals working with the patient. Well lit rooms and the use of glasses and hearing aids can help to reduce hallucinations. Cholinesterase inhibitors used in Alzheimer's disease have a role in DLB and PDD. Trials show moderate improvements in cognitive function in patients treated with rivastigmine. The greatest impact, however, seems to be on the psychotic features of the disease. Patients with DLB are less likely to have a good motor response from L-dopa than patients with Parkinson's disease or PDD.
Normal cognitive decline or dementia?
Cognitive speed, inhibitory function, and memory decline with age while crystallised, particularly verbal, abilities remain largely intact. Poor health, fewer years of education, lower activity, the presence of the APOE E4 allele, and high BP appear to predict faster cognitive decline. Dementia is diagnosed in the presence of objective cognitive impairment, both long- and short-term memory, plus at least one additional (cortical) cognitive deficit, such as dysphasia, dyspraxia, agnosia, or disturbance in executive functioning. In addition, patients have to show significant impairment in social or occupational functioning and a significant decline from previous levels. Both smoking and diabetes increase the risk of all types of dementia, not smoking or even stopping smoking reduces this risk, but better control of type 2 diabetes does not appear to have a measurable effect. Drinking small to moderate amounts of alcohol appears to confer some benefit in ameliorating cognitive decline. There is some evidence that HRT, DHEA, BP lowering in patients without prior cerebrovascular disease, statins, vitamin B6 and procaine are NOT helpful. There is insufficient evidence to establish or refute a beneficial effect for exercise, treatment of type 2 diabetes, omega-3 fatty acids, folic acid with/without vitamin B12, antioxidant vitamins, or ginkgo biloba. Depressive symptoms are more prevalent than dementia. Clinical (major) depression can present with cognitive deterioration, often associated with subjective complaints. Patients with subjective or objective memory impairment, but without functional deterioration, can be referred to the local memory clinic, while demented patients eligible for acetylcholinesterase inhibitor treatment, patients whose diagnosis is unclear and who may need some specific investigations, as well as patients who may benefit from a combined approach with psychotropic drugs and behavioural support should be referred to the local mental health team.
Dual task performance in early Alzheimer's disease, amnestic mild cognitive impairment and depression.
BACKGROUND: The dual task paradigm (Baddeley et al. 1986; Della Sala et al. 1995) has been proposed as a sensitive measure of Alzheimer's dementia, early in the disease process. METHOD: We investigated this claim by administering the modified dual task paradigm (utilising a pencil-and-paper version of a tracking task) to 33 patients with amnestic mild cognitive impairment (aMCI) and 10 with very early Alzheimer's disease, as well as 21 healthy elderly subjects and 17 controls with depressive symptoms. All groups were closely matched for age and pre-morbid intellectual ability. RESULTS: There were no group differences in dual task performance, despite poor performance in episodic memory tests of the aMCI and early Alzheimer's disease groups. In contrast, the Alzheimer patients were specifically impaired in the trail-making test B, another commonly used test of divided attention. CONCLUSIONS: The dual task paradigm lacks sensitivity for use in the early differential diagnosis of Alzheimer's disease.
Clinical referral patterns and cognitive profile in mild cognitive impairment.
BACKGROUND: There is current interest in exploring the different subtypes of mild cognitive impairment (MCI), in terms of both their epidemiology and their cognitive profile. AIMS: To examine the frequency of MCI subtypes presenting to a memory clinic and to document detailed neuropsychological profiles of patients with the amnestic subtype. METHOD: Consecutive tertiary referrals (n=187) were psychiatrically evaluated; 45 patients met criteria for amnestic mild cognitive impairment (aMCI). A subgroup of 33 patients with aMCI as well as 21 healthy controls took part in a thorough neuropsychological examination. RESULTS: Of the patients who were examined in greater neuropsychological detail, ten had pure aMCI (none with visual memory impairment only). Fifteen met criteria for non-amnestic MCI. Fifteen had normal neuropsychological profiles. Using more than one test increased sensitivity to detect episodic memory impairment. CONCLUSIONS: Amnestic MCI is an important diagnosis in secondary and tertiary memory clinics. There is scope to improve the efficacy and sensitivity of the clinical assessment of this impairment.
Predicting schizophrenia: findings from the Edinburgh High-Risk Study.
BACKGROUND: The hypothesis that schizophrenia is neurodevelopmental was investigated in a prospective study of young people with a postulated 10-15% risk for the development of schizophrenia. AIMS: To determine premorbid variables distinguishing high-risk people who will go on to develop schizophrenia from those who will not. METHOD: A high-risk sample of 163 young adults with two relatives with schizophrenia was recruited. They and 36 controls were serially examined. Baseline measures were compared between those who did develop schizophrenia, a well control group, a well high-risk group and high-risk participants with partial or isolated psychotic symptoms. RESULTS: Of those at high risk, 20 developed schizophrenia within 2(1/2) years. More experienced isolated or partial psychotic symptoms. Those who developed schizophrenia differed from those who did not on social anxiety, withdrawal and other schizotypal features. The whole high-risk sample differed from the control group on developmental and neuropsychological variables. CONCLUSIONS: The genetic component of schizophrenia affects many more individuals than will develop the illness, and partial impairment can be found in them. Highly significant predictors of the development of schizophrenia are detectable years before onset.
Direct comparison of spatially normalized PET and SPECT scans in Alzheimer's disease.
UNLABELLED: Hexamethylpropyleneamine oxime (HMPAO) SPECT and 18F-FDG PET depict similar aspects of perfusion and metabolic abnormalities in Alzheimer's disease (AD), but the correspondence between them is not known in detail. We therefore used statistical parametric mapping to detect and compare abnormal brain areas objectively and quantitatively. METHODS: Twenty-six patients with probable AD (mean age +/- SD, 66 +/- 9 y; mean Mini-Mental State Examination score, 22.5 +/- 4.2) and 6 nondemented healthy volunteers (mean age, 63 +/- 11 y) were studied with HMPAO SPECT and 18F-FDG PET. All images underwent the same processing steps, including 12-mm gaussian smoothing, spatial normalization, and z transformation with respect to normal average and SD. Thresholding of z maps was used to detect abnormal voxels. RESULTS: The overall correlation between PET and SPECT across the entire brain was significant but not close (average r = 0.43). The best correspondence was found in the temporoparietal and posterior cingulate association cortices. There, the number of abnormal voxels for PET correlated strongly with the number for SPECT (r = 0.90 at a z threshold of -2.25), but tracer uptake reductions were significantly more pronounced for PET than for SPECT. Discordant findings were most frequently seen in the temporobasal and orbitofrontal areas (PET low, SPECT high) and in the cerebellum, parahippocampal cortex, and midcingulate cortex (PET high, SPECT low). The correlation between dementia severity and the number of abnormal voxels was closer for PET than for SPECT. Separation of patients from healthy volunteers by counting the number of abnormal voxels was possible over a much wider range of z thresholds with PET than with SPECT. CONCLUSION: Correspondence between 18F-FDG PET and HMPAO SPECT is limited to the main finding of temporoparietal and posterior cingulate functional impairment in mild to moderate AD. The distinction between healthy volunteers and patients is less sensitive to threshold selection with PET than with SPECT, and findings in the frontal, temporobasal, and temporomesial cortices and in the cerebellum may differ between the 2 techniques.
The effects of noradrenergic re-uptake inhibition on memory encoding in man.
RATIONALE: Animal and human evidence implicate the central noradrenergic system in the process of memory modulation for emotional material. Blockade of the beta-adrenergic system in humans has been shown to result in decreased recall and recognition memory performance, relative to placebo, for the emotional elements of a series of slides accompanied by a narrative. Stimulation of the noradrenergic system with yohimbine has also been shown to result in increased recall and recognition performance relative to placebo for the same stimulus materials. OBJECTIVES: The present study tested the hypothesis that stimulating the central noradrenergic system using the new noradrenaline re-uptake inhibitor reboxetine would result in a dose-dependent enhancement of memory for emotional material in man. METHODS: The central noradrenergic system was manipulated using reboxetine in a double-blind, randomised between-group, placebo-controlled design with 36 healthy adult subjects in each of three groups (placebo, 4 and 8 mg reboxetine). Free recall and recognition memory performance were assessed in a 'surprise' memory test following a 7-day interval. RESULTS: We found no memory enhancing effect of reboxetine. In contrast we observed a dose-dependent effect on memory opposite to the predicted direction. There were no significant differences between groups in self-rated stress and arousal scores or self-rated emotional reactions to the stimuli. All groups showed the expected increased memory performance for the middle 'emotive' phase of the story. CONCLUSION: Selective stimulation of the central noradrenergic system at encoding did not result in enhanced long-term memory for emotional material in man.
Abnormal response to negative feedback in depression.
BACKGROUND: Recent studies have suggested that subjects with depression suffer a diagnosis-specific motivational deficit, characterized by an abnormal response to negative feedback that endures beyond clinical recovery. Furthermore, it has been suggested that negative feedback may motivate non-depressed controls, but not depressed patients, to improve their performance in neuropsychological tests. METHODS: We describe two studies. The first compared performance on the simultaneous and delayed match to sample (SDMS) task from the CANTAB neuropsychological test battery, in 20 patients with severe depression with 20 with acute schizophrenia, 40 with chronic schizophrenia and 40 healthy controls. The second examined the performance of depressed patients with diurnal variation in symptoms and cognitive function. RESULTS: All patients groups showed impairments on the simultaneous and delayed match to sample task compared to controls. Depressed patients did not show an abnormal response to negative feedback. Controls did not show a motivational effect of negative feedback. Depressed patients with diurnal variation showed no variation in their response to perceived failure. There was no evidence of abnormal response to negative feedback in any patient group using the 'runs test' or of a motivational effect in controls. Conditional probability analysis was not independent of the total number of errors made in the SDMS task. CONCLUSIONS: Further studies are suggested to examine whether an abnormal response to negative feedback characterizes particular subgroups of patients suffering from depression.
A double-blind, placebo-controlled study of tacrine in patients with Alzheimer's disease using SPET.
BACKGROUND: the effect of single-dose and long-term cholinergic enhancement with tacrine on regional cerebral perfusion was examined in patients with Alzheimer's disease using single-photon emission tomography (SPET). METHOD: 23 patients with probable Alzheimer's disease (DSM-III-R and NINCDS-ADRDA criteria) were scanned before and after a single oral dose of tacrine at the start of the study and again after 12 weeks of randomized, double-blind treatment with tacrine or placebo, using high resolution (99m)Tc-Exametazime SPET. Patients also underwent neuropsychological testing with the CAMCOG, the Mini-Mental State Examination and the Rivermead Behavioural Memory Test before and after 12 weeks of treatment. RESULTS: occipital count ratios in all regions of interest declined by 3% over 12 weeks, indicating a progression of the disease. Acute tacrine challenge resulted in a 16% increase in the superior frontal and a 11% decrease in the anterior temporal cortex. The acute effects of tacrine were modified by 12 weeks of treatment, particularly in the medial frontal (cingulate) cortex where active treatment was associated with a reduced acute tacrine response. There were no changes in cognitive function associated with active treatment. CONCLUSION: the study demonstrates the sensitivity of cerebral perfusion measures to changes during acute and medium-term tacrine treatment.
Short-term effects of electroconvulsive treatment on the uptake of 99mTc-exametazime into brain in major depression shown with single photon emission tomography.
Fifteen patients with major depression who were being treated with bilateral electroconvulsive treatment (ECT) were investigated before and 45 min after a single ECT using split-dose Single Photon Emission Tomography (SPET or SPECT) with 99mTc-Exametazime. All patients suffered from unipolar depressive illness and were rated on the Newcastle scale and with the 17-item Hamilton scale. They completed tests of orientation and verbal memory on the day of ECT. For comparison, verbal memory was also tested on the preceding day. The uptake of 99mTc-Exametazime was expressed relative to calcarine/occipital cortex. Significant decreases in tracer uptake were confined to the inferior anterior cingulate cortex. The changes were correlated with the severity of depressive symptoms and more weakly with decrements of memory function produced by ECT; there was no significant correlation with stimulus intensity or electroencephalographic measures of seizure duration.
The clinical manifestation of mental disorder in Huntington's disease: a retrospective case record study of disease progression.
All cases (86) of Huntington's Disease presenting between 1970 and 1987 in the Grampian Health Board region were identified and a case note analysis of neurological and psychiatric syndromes carried out--the latter using the PSE syndrome check-list. The commonest syndromes were organic impairment, irritability, loss of interest and concentration and simple depression and these were often the presenting psychiatric syndromes. General anxiety, worrying and social unease occurred early, commonly before movement disorder and were associated with longer survival.
MRI correlates of episodic memory in Alzheimer's disease, mild cognitive impairment, and healthy aging.
Episodic memory is a core feature of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Impaired episodic memory in AD results from the dysfunction of an integrated network and involves both gray and white matter pathologies. We explored the neural correlates of episodic memory in AD, MCI and healthy aging by correlating a measure of episodic memory with hippocampal volume and fractional anisotropy (FA) and mean diffusivity (MD) of the cingulum and fornix. Episodic memory was associated with hippocampal volume and MD of the cingulum and fornix. In contrast, there were fewer significant associations between episodic memory and FA. These findings support a relationship between episodic memory and hippocampal circuitry, and suggest that MD is a more sensitive marker of decreased white matter integrity in the study of AD and MCI than FA. Furthermore, MD was significantly associated with hippocampal volume, indicating that white matter pathology is not completely independent of gray matter pathology. However, the pattern of diffusivity differences in AD and MCI implies a more complex pathology than simply Wallerian degeneration.
Predicting the accuracy of a diagnosis of Alzheimer's disease with 99mTc HMPAO single photon emission computed tomography.
The current clinical practice of reporting images obtained with single photon emission computed tomography (SPECT) with 99mTc-d,l-hexamethylpropylene amine oxime (99mTc HMPAO) images was examined by having 16 experts evaluate the appearance of SPECT images in patients with probable Alzheimer type dementia (ATD), patients with major depressive episode (DSM-IV), and healthy volunteers. The experts rated diagnostic criteria of scan appearance in respect of importance for their individual diagnostic practice. Experts were nuclear medicine specialists, psychiatrists and physicists taking part in a European multi-centre collaborative project. They examined 158 perfusion scans and then the same perfusion scans together with statistical parametric maps (SPMs). The sensitivity of experts' diagnostic judgments was significantly and negatively correlated with the importance they attributed to reduced regional perfusion in the parietal lobes. A corresponding positive correlation was observed for diagnostic specificity against depressed and healthy volunteers. Similar results were observed with SPMs, where in addition area under the receiver operating characteristic (ROC) curve was significantly reduced with raters' increased diagnostic reliance on frontal lobe perfusion deficits. Sensitivity was greater with SPM for patients younger than 70 years and with dementia severity. The more importance experts placed on parietal (symmetrical) perfusion deficits, the less sensitive and the more specific their diagnostic judgment was. Using multiple raters in large patient samples may provide a way of identifying successful explicit diagnostic strategies for clinical image analysis.