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.

Cerebral perfusion correlates of depressed mood.

BACKGROUND: The spontaneous diurnal variation of mood and other symptoms provides a substrate for the examination of the relationship between symptoms and regional brain activation in depression. METHOD: Twenty unipolar depressed patients with diurnal variation of mood were examined at 8 a.m. and 8 p.m. with neuropsychological measures, clinical ratings and single photon emission tomography (SPET). Brain perfusion maps were spatially transformed into standard stereotactic space and compared pixel-by-pixel. A parametric (correlational) analysis was used to examine the relationship between symptom severity and brain perfusion, both between and within subjects. RESULTS: Global depression severity and an independent 'vital' depression factor were associated in subjects with increased perfusion in cingulate and other paralimbic areas. In addition there was a probable association between an increase in an anxious-depression factor and reduced frontal neocortical perfusion. CONCLUSIONS: Depressive symptom changes are associated with metabolic changes in the cingulate gyrus and associated paralimbic structures.

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.

An analysis of memory dysfunction in major depression.

15 patients suffering from DSM-III-R major depression were compared with 15 age-, sex- and intelligence-matched controls on a battery of memory tests, aimed at fractionating memory dysfunction in depression. Patients were unimpaired relative to controls on measures of short-term memory, recognition, semantic memory and implicit memory. There was no evidence of a hedonic bias in recall of positive vs. negatively valenced stimuli, nor was there any correlation between depression severity and level of memory impairment. Psychotic patients did not demonstrate greater memory impairment relative to nonpsychotic depressed patients. As a group, however, depressed patients demonstrated deficits in psychomotor speed and in free recall of material (both immediate and delayed). The selective recall deficit suggests that material has been encoded but that patients are particularly impaired with regard to search and retrieval processes.

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.

Effects of fluvoxamine treatment on cognitive functioning in the alcoholic Korsakoff syndrome.

Eight patients suffering from the alcoholic Korsakoff syndrome (AKS) were entered in a double-blind cross-over trial of fluvoxamine 200 mg per day for 4 weeks versus matched placebo for 4 weeks. At the end of each phase, patients were assessed using a detailed neuropsychological test battery. Verbal fluency performance was significantly impaired following fluvoxamine treatment. No significant differences emerged on any of the other cognitive test measures when fluvoxamine was compared with placebo. However, two of the patients developed a major depressive episode while receiving fluvoxamine.

The differentiation of major depression from dementia of the Alzheimer type using within-subject neuropsychological discrepancy analysis.

The method of comparing premorbid versus current intellectual ability has become established clinical practice in the differential diagnosis of dementia versus depression. Recently, Schlosser & Ivison (1989) suggested that the comparison of premorbid ability versus current memory function may offer a more sensitive method of assessing early dementia. In the present study, a variety of within-subject discrepancy analyses comparing premorbid estimates with current measures of memory and intellectual functioning were compared across three groups: patients with dementia of the Alzheimer type, patients with major depression and healthy controls. The results revealed that, while mean group differences were easily demonstrated, the overlap between Alzheimer and depressed patients was large. It is concluded that none of the simple neuropsychological discrepancy analyses examined in the present study can be recommended for use in clinical practice for the differential diagnosis of dementia from major depression.

The effect of anxiety induction on the regional uptake of 99mTc-exametazime in simple phobia as shown by single photon emission tomography (SPET).

Ten patients suffering from DSM-III-R simple phobia were studied under two conditions: (a) while listening to a 4 min relaxation tape, and (b) while listening to a 4 min audio tape describing exposure to the phobic stimulus. During each condition, subjects were injected with 99mTc-Exametazime, a marker of regional cerebral blood flow. Subjective and psychophysiological measures indicated a marked effect of the anxiety induction procedure. Ratio analysis of the SPET data revealed reductions in tracer uptake largely confined to posterior cerebral regions bilaterally. Analysis of brain regions of interest normalised to the whole brain slice showed reductions confined to right temporal/occipital regions. In general there was no clear association between subjective and physiological variables and changes in regional uptake of tracer as a consequence of the anxiety induction procedure. The changes in tracer uptake were dissimilar to those previously reported for other cognitive activation paradigms, providing some reassurance that those functional brain changes were not artefacts of non-specific changes in state anxiety. These posterior brain changes may reflect alterations in activation of the GABA/benzodiazepine complex.

Single-photon emission computed tomography with 99mTc-exametazime in unmedicated schizophrenic patients.

We examined 20 actively psychotic unmedicated schizophrenic patients and 20 matched control subjects by using single-photon emission, computed tomography (SPECT) with 99mtechnetium-exametazime. Patients showed a hyperfrontal pattern of tracer uptake with significant relative increases in superior prefrontal cortex. This abnormality was less pronounced in patients with higher symptom scores for psychomotor poverty. In addition, patients showed associations between certain schizophrenic syndrome scores, such as psychomotor poverty, disorganization, and reality distortion, and tracer uptake to a number of cortical and subcortical brain regions. This syndrome-related pattern of tracer uptake was, at least in part, consistent with similar associations previously reported in chronically medicated schizophrenic patients. SPECT therefore provides a readily available method to examine the relationship between symptom pattern and regional brain metabolism in psychotic patients. Any observed patterns of association will depend on the current mental and medication status of the patients examined.