Predictors of the discrepancy between objective and subjective cognition in bipolar disorder: a novel methodology.

OBJECTIVE: The poor relationship between subjective and objective cognitive impairment in bipolar disorder (BD) is well-established. However, beyond simple correlation, this has not been explored further using a methodology that quantifies the degree and direction of the discrepancy. This study aimed to develop such a methodology to explore clinical characteristics predictive of subjective-objective discrepancy in a large BD patient cohort. METHODS: Data from 109 remitted BD patients and 110 healthy controls were pooled from previous studies, including neuropsychological test scores, self-reported cognitive difficulties, and ratings of mood, stress, socio-occupational capacity, and quality of life. Cognitive symptom 'sensitivity' scores were calculated using a novel methodology, with positive scores reflecting disproportionately more subjective complaints than objective impairment and negative values reflecting disproportionately more objective than subjective impairment ('stoicism'). RESULTS: More subsyndromal depressive and manic symptoms, hospitalizations, BD type II, and being male positively predicted 'sensitivity', while higher verbal IQ predicted more 'stoicism'. 'Sensitive' patients were characterized by greater socio-occupational difficulties, more perceived stress, and lower quality of life. CONCLUSION: Objective neuropsychological assessment seems especially warranted in patients with (residual) mood symptoms, BD type II, chronic illness, and/or high IQ for correct identification of cognitive deficits before commencement of treatments targeting cognition.

Daily electronic self-monitoring in bipolar disorder using smartphones - the MONARCA I trial: a randomized, placebo-controlled, single-blind, parallel group trial.

BACKGROUND: The number of studies on electronic self-monitoring in affective disorder and other psychiatric disorders is increasing and indicates high patient acceptance and adherence. Nevertheless, the effect of electronic self-monitoring in patients with bipolar disorder has never been investigated in a randomized controlled trial (RCT). The objective of this trial was to investigate in a RCT whether the use of daily electronic self-monitoring using smartphones reduces depressive and manic symptoms in patients with bipolar disorder. METHOD: A total of 78 patients with bipolar disorder according to ICD-10 criteria, aged 18-60 years, and with 17-item Hamilton Depression Rating Scale (HAMD-17) and Young Mania Rating Scale (YMRS) scores ≤17 were randomized to the use of a smartphone for daily self-monitoring including a clinical feedback loop (the intervention group) or to the use of a smartphone for normal communicative purposes (the control group) for 6 months. The primary outcomes were differences in depressive and manic symptoms measured using HAMD-17 and YMRS, respectively, between the intervention and control groups. RESULTS: Intention-to-treat analyses using linear mixed models showed no significant effects of daily self-monitoring using smartphones on depressive as well as manic symptoms. There was a tendency towards more sustained depressive symptoms in the intervention group (B = 2.02, 95% confidence interval -0.13 to 4.17, p = 0.066). Sub-group analysis among patients without mixed symptoms and patients with presence of depressive and manic symptoms showed significantly more depressive symptoms and fewer manic symptoms during the trial period in the intervention group. CONCLUSIONS: These results highlight that electronic self-monitoring, although intuitive and appealing, needs critical consideration and further clarification before it is implemented as a clinical tool.

Altered reward processing in the orbitofrontal cortex and hippocampus in healthy first-degree relatives of patients with depression.

BACKGROUND: Healthy first-degree relatives of patients with major depression (rMD+) show brain structure and functional response anomalies and have elevated risk for developing depression, a disorder linked to abnormal serotonergic neurotransmission and reward processing. METHOD: In a two-step functional magnetic resonance imaging (fMRI) investigation, we first evaluated whether positive and negative monetary outcomes were differentially processed by rMD+ individuals compared to healthy first-degree relatives of control probands (rMD-). Second, in a double-blinded placebo-controlled randomized trial we investigated whether a 4-week intervention with the selective serotonergic reuptake inhibitor (SSRI) escitalopram had a normalizing effect on behavior and brain responses of the rMD+ individuals. RESULTS: Negative outcomes increased the probability of risk-averse choices in the subsequent trial in rMD+ but not in rMD- individuals. The orbitofrontal cortex (OFC) displayed a stronger neural response when subjects missed a large reward after a low-risk choice in the rMD+ group compared to the rMD- group. The enhanced orbitofrontal response to negative outcomes was reversed following escitalopram intervention compared to placebo. Conversely, for positive outcomes, the left hippocampus showed attenuated response to high wins in the rMD+ compared to the rMD- group. The SSRI intervention reinforced the hippocampal response to large wins. A subsequent structural analysis revealed that the abnormal neural responses were not accounted for by changes in gray matter density in rMD+ individuals. CONCLUSIONS: Our study in first-degree relatives of depressive patients showed abnormal brain responses to aversive and rewarding outcomes in regions known to be dysfunctional in depression. We further confirmed the reversal of these aberrant activations with SSRI intervention.

The cumulative load of depressive illness is associated with cognitive function in the remitted state of unipolar depressive disorder.

OBJECTIVE: To investigate whether the cumulative number, duration and subtypes (severity and presence of psychotic features) of previous episodes of depression in patients with unipolar depressive disorder in a remitted state are associated with decreased global cognitive function. METHODS: Via the Danish registers individuals between 40 and 80 years of age were identified: (1) patients with a diagnosis of unipolar disorder at their first discharge from a psychiatric hospital in the period 1994 to 2002, and (2) gender and age matched control individuals. The participants were assessed with the Cambridge Cognitive Examination (CAMCOG), which provides a composite measure of global cognitive function. RESULTS: A total of 88 patients and 50 controls accepted our invitation to participate, fulfilled the selection criteria and were included in the study. The cumulative duration of depressive episodes was associated with a decreased CAMCOG score adjusted for age, gender, education, premorbid IQ and residual depressive symptoms (B=-0.14, 95% C.I. (-0.26, -0.02), R(2)adj=0.31, P=.02). Significant associations were also found between CAMCOG score and the cumulative duration and total number of depressive episodes with psychotic features, respectively. CONCLUSION: Our findings suggest that cognitive dysfunction is associated with the cumulative duration of depressive episodes, and that, in particular, depressive episodes with psychotic features in the course of illness may be a significant predictor of future impairment of cognitive function.

Differences in seed rain composition in small and large fragments in the northeast Brazilian Atlantic Forest.

Tropical forests are seriously threatened by fragmentation and habitat loss. The impact of fragment size and forest configuration on the composition of seed rain is insufficiently studied. For the present study, seed rain composition of small and large forest fragments (8-388 ha) was assessed in order to identify variations in seed abundance, species richness, seed size and dispersal mode. Seed rain was documented during a 1-year period in three large and four small Atlantic Forest fragments that are isolated by a sugarcane matrix. Total seed rain included 20,518 seeds of 149 species of trees, shrubs, palms, lianas and herbs. Most species and seeds were animal-dispersed. A significant difference in the proportion of seeds and species within different categories of seed size was found between small and large fragments. Small fragments received significantly more very small-sized seeds (<0.3 cm) and less large-seeded species (>1.5 cm) that were generally very rare, with only one species in small and eight in large fragments. We found a negative correlation between the inflow of small-sized seeds and the percentage of forest cover. Species richness was lower in small than in large fragments, but the difference was not very pronounced. Given our results, we propose changing plant species pools through logging, tree mortality and a high inflow of pioneer species and lianas, especially in small forest fragments and areas with low forest cover. Connecting forest fragments through corridors and reforestation with local large-seeded tree species may facilitate the maintenance of species diversity.

Decreased levels of brain-derived neurotrophic factor in the remitted state of unipolar depressive disorder.

OBJECTIVE: Decreased levels of peripheral brain-derived neurotrophic factor (BDNF) have been associated with depression. It is uncertain whether abnormally low levels of BDNF in blood are present beyond the depressive state and whether levels of BDNF are associated with the course of clinical illness. METHOD: Whole-blood BDNF levels were measured in blood samples from patients with unipolar disorder in a sustained state of clinical remission and in a healthy control group. Participants were recruited via Danish registers, a method that benefits from the opportunity to obtain well-matched community-based samples as well as providing a high diagnostic validity of the patient sample. RESULTS: A total of 85 patients and 50 controls were included in the study. In multiple linear regression analyses, including the covariates age, gender, 17-item Hamilton Depression Rating Scale scores, body-mass index, education, smoking and physical exercise, patients with unipolar depressive disorder had decreased levels of BDNF compared to healthy control individuals [B = -7.4, 95% CI (-11.2, -3.7), = 0.21 P < 0.001]. No association between course of clinical illness and BDNF levels was present. CONCLUSION: Whole-blood BDNF levels seem to be decreased in patients remitted from unipolar depressive disorder, suggesting that neurotrophic changes may exist beyond the depressive state.

[Extracorporeal shockwave therapy in symptomatic heel spurs. An overview]. / Extrakorporale Stosswellentherapie beim symptomatischen Fersensporn. Eine Ubersicht.

Extracorporeal shock wave application (ESWA) has been successfully used for years in routine clinical management of plantar fasciitis. So far no clinical trails have shown the efficiency in placebo-controlled protocols. This paper presents an overview of conservative and operative treatment modalities with respect to their efficacy. Results of a prospective randomized placebo-controlled double-blind multicenter trial to show efficiency and safety of ESWT are presented. In patients treated conservatively without success, a single shock wave application can improve the condition significantly compared with placebo treatment (p = 0.0149). The Roles and Maudsley score also showed a significant improvement between the groups, with 61.6% good or excellent results in the verum group and 39.7% in the placebo group (p = 0.0128). Therapy-related side effects (local swelling, petechia) are rare. The data presented in this study led to FDA approval in January 2002 of the shock wave device used.

Cerebral networks in sensorimotor disturbances.

Increasing evidence suggests that the human brain employs multiple, interconnected brain areas for information processing and control of behavior, including the performance of laboratory tasks. Brain diseases are expected to affect these networks directly by interference and indirectly as a consequence of deficit compensation. Covariance analyses applied to functional brain imaging data open the opportunity to study neural networks and their disease-related changes in the human brain. Here, we review our analytic approach based on principal component analysis (PCA) to address such questions. We will discuss its methodological foundations and applications in patients with sensorimotor disorders. We will show that PCA in combination with, both, hypothesis-driven testing and correlation statistics provides a powerful tool for elucidating disease-related abnormalities and postlesional reorganization of neural networks in the human brain.

Disturbed functional brain interactions underlying deficient tactile object discrimination in Parkinson's disease.

Somatosensory discrimination of cuboid objects was studied in a group of healthy volunteers and patients with Parkinson's disease using regional cerebral blood flow (rCBF) measurements obtained with positron emission tomography (PET) and 15O labeled water [H2 15O]. A 6-[18F]-fluoro-L-dopa (FDOPA) PET scan demonstrated that the patients may be grouped into those with normal and those with abnormally lowA FDOPA uptake in the caudate nucleus. The categorical group comparisons revealed that task-induced rCBF increases were deficient in bilateral motor and sensory cortical areas in the Parkinson patients. Moreover, deficient rCBF increases were evident in the mesial and right dorsolateral prefrontal cortex for patients in a more advanced disease state, who showed low FDOPA uptake in the caudate nucleus. A principal component analysis (PCA), performed on the rCBF data, identified three patterns (principal components, PCs) that differentiated patients from normals. The first PC represented a right-hemisphere dominant, bilateral group of brain areas known to be involved in tactile exploration. A second PC reflected a cortical-subcortical pattern of functional interactions, comprising cortical areas important for working memory processes. The third group-differentiating PC revealed a pattern of functional interactions involving bilateral temporo-parieto-occipital association cortices, which was consistent with a hypothesized supramodal network necessary for object discrimination. In an additional subgroup analysis, greater expression of the third PC pattern predicted greater caudate FDOPA uptake in patients. Our neuroimaging data revealed a disturbance of distinct patterns of brain functional interactions related to the sensorimotor deficit in Parkinson's disease and to deficits of cognitive information processing deficits in the more advanced stage of Parkinson's disease.

Corpus callosum size in children with developmental language disorder.

Using high-resolution in-vivo magnetic resonance morphometry of the midsagittal area of the corpus callosum (CC) and four callosal subareas in 21 children with developmental language disorder (DLD) of the phonologic-syntactic type we found no significant anatomical differences in comparison to an age- and gender-matched normal control group. There was also no significant between-group difference when the approximately 7% smaller forebrain volume among children with DLD was accounted for by relating CC measures to forebrain volume. Only a tendency towards a larger anterior and middle CC in relation to forebrain volume was found in DLD children. In our DLD children we found the same relationship between CC midsagittal size and forebrain volume as recently reported for normal adults, namely, that the CC area increases to the two-third power of forebrain volume.

The role of diaschisis in stroke recovery.

BACKGROUND AND PURPOSE: Recovery from hemiparesis after stroke has been shown to involve reorganization in motor and premotor cortical areas. However, whether poststroke recovery also depends on changes in remote brain structures, ie, diaschisis, is as yet unresolved. To address this question, we studied regional cerebral blood flow in 7 patients (mean+/-SD age, 54+/-8 years) after their first hemiparetic stroke. METHODS: We analyzed imaging data voxel by voxel using a principal component analysis by which coherent changes in functional networks could be disclosed. Performance was assessed by a motor score and by the finger movement rate during the regional cerebral blood flow measurements. RESULTS: The patients had recovered (P<0. 001) from severe hemiparesis after on average 6 months and were able to perform sequential finger movements with the recovered hand. Regional cerebral blood flow at rest differentiated patients and controls (P<0.05) by a network that was affected by the stroke lesion. During blindfolded performance of sequential finger movements, patients were differentiated from controls (P<0.05) by a recovery-related network and a movement-control network. These networks were spatially incongruent, involving motor, sensory, and visual cortex of both cerebral hemispheres, the basal ganglia, thalamus, and cerebellum. The lesion-affected and recovery-related networks overlapped in the contralesional thalamus and extrastriate occipital cortex. CONCLUSIONS: Motor recovery after hemiparetic brain infarction is subserved by brain structures in locations remote from the stroke lesion. The topographic overlap of the lesion-affected and recovery-related networks suggests that diaschisis may play a critical role in stroke recovery.

Reorganized cerebral metabolic interactions in temporal lobe epilepsy.

Patients with left temporal lobe epilepsy demonstrate language impairments that are not well understood. To explore abnormal patterns of brain functional connections with respect to language processing, we applied a principal component analysis to resting regional cerebral metabolic data obtained with positron emission tomography in patients with right- and left-sided temporal lobe epilepsy and controls. Two principal components were expressed differentially among the groups. One principal component comprised a pattern of metabolic interactions involving left inferior frontal and left superior temporal regions-corresponding to Broca's and Wernicke's areas, respectively-and right mesial temporal cortex and right thalamus. Functional couplings between these brain regions were abnormally enhanced in the left-sided epilepsy patients. The right thalamic left superior temporal coupling was also abnormally enhanced in the right-sided epilepsy patients, but differentially from that in the left-sided patients. The other principal component was characterized by a pattern of metabolic interactions involving right and left mid prefrontal and right superior temporal cortex. Although both the right- and left-sided epilepsy patients showed decreased functional couplings between left mid prefrontal and the other brain regions, a weaker right-left mid prefrontal coupling in the left-sided epilepsy patients best distinguished them from the right-sided patients. The two mutually independent, abnormal metabolic patterns each predicted verbal intelligence deficits in the patients. The findings suggest a site-dependent reorganization of two independent, language-subserving pathways in temporal lobe epilepsy.

On two methods of statistical image analysis.

The computerized brain atlas (CBA) and statistical parametric mapping (SPM) are two procedures for voxel-based statistical evaluation of PET activation studies. Each includes spatial standardization of image volumes, computation of a statistic, and evaluation of its significance. In addition, smoothing and correcting for differences of global means are commonly performed in SPM before statistical analysis. We report a comparison of methods in an analysis of regional cerebral blood flow (rCBF) in 10 human volunteers and 10 simulated activations. For the human studies, CBA or linear SPM standarization methods were followed by smoothing and computation of a statistic with the paired t-test of CBA or general linear model of SPM. No standardization, linear, and nonlinear SPM standardization were applied to the simulations. Significance of the statistic was evaluated using the cluster-size method common to SPM and CBA. SPM employs the theory of Gaussian random fields to estimate the cluster size distributions; simulations described in the Appendix provided empirical distributions derived from t-maps. The quantities evaluated were number and size of functional regions (FRs), maximum statistic, average resting rCBF, and percentage change. For the simulations, the efficiency of signal detection and rate of false positives could be evaluated as well as the distributions of statistics and cluster size in the absence of signal. The similarity of the results yielded by similar methods of analysis for the human studies and the simulated activations substantiates the robustness of the methods for selecting functional regions. However, the analysis of simulated activations demonstrated that quantitative evaluation of significance of a functional region encounters important obstacles at every stage of the analysis.

Multimodal output mapping of human central motor representation on different spatial scales.

1. Non-invasive mapping by focal transcranial magnetic stimulation (TMS) is frequently used to investigate cortical motor function in the intact and injured human brain. We examined how TMS-derived maps relate to the underlying cortical anatomy and to cortical maps generated by functional imaging studies. 2. The centres of gravity (COGs) of TMS maps of the first dorsal intersosseus muscle (FDI) were integrated into 3-D magnetic resonance imaging (MRI) data sets in eleven subjects. In seven of these subjects the TMS-derived COGs were compared with the COG of regional cerebral blood flow increases using positron emission tomography (PET) in an index finger flexion protocol. 3. Mean TMS-derived COG projections were located on the posterior lip of the precentral gyrus and TMS-derived COG projections were in close proximity to the mean PET-derived COG, suggesting that the two methods reflect activity of similar cortical elements. 4. Criteria for a reliable assessment of the COG and the number of positions with a minimum amplitude of two-thirds of the maximum motor-evoked potential (T3Ps) were determined as a function of the number of stimuli and extension of the stimulation field. COGs and T3Ps were compared with an estimate of the size of the human motor cortex targeting alpha-motoneurons of forearm muscles. This comparison suggests that TMS can retrieve spatial information on cortical organization below the macroanatomic scale of cortical regions. 5. Finally, we studied the cortical representation of hand muscles in relation to facial and foot muscle representations and investigated hemispherical asymmetries. We did not find any evidence for a different ipsi- or contralateral representation of the mentalis muscle. Also, no difference was found between FDI representations on the dominant versus the non-dominant hemisphere.

Precentral glioma location determines the displacement of cortical hand representation.

OBJECTIVE: Low-grade brain tumors may remain asymptomatic in contrast to malignant gliomas. The mechanisms underlying the preservation of cerebral function in such gliomas are not well understood. METHODS: We used positron emission tomography and transcranial magnetic stimulation for presurgical monitoring of motor hand function in six patients with gliomas of the precentral gyrus. All patients were able to perform finger movements of the contralesional hand. RESULTS: Movement-related increases of the regional cerebral blood flow occurred only outside the tumor in surrounding brain tissue. Compared with the contralateral side, these activations were shifted by 20 +/- 13 mm (standard deviation) within the dorsoventral dimension of the precentral gyrus. This shift of cortical hand representation could not be explained by the deformation of the central sulcus as determined from the spatially aligned magnetic resonance images but was closely related to the location of the maximal tumor growth. Dorsal tumor growth resulted in ventral displacement of motor hand representation, leaving the motor cortical output system unaffected, whereas ventral tumor growth leading to dorsal displacement of motor hand representation compromised the motor cortical output, as evident from transcranial magnetic stimulation. In two patients, additional activation of the supplementary motor area was present. CONCLUSION: Our data provide evidence for the reorganization of the human motor cortex to allow for preserved hand function in Grade II astrocytomas.

[Prostate-specific antigen, acid phosphatases and rectal exploration in the diagnosis of prostatic cancer]. / Prostataspecifikt antigen, sure fosfataser og rektaleksploration i diagnostik af cancer prostatae.

Eleven hundred and seven patients referred for urological evaluation including measurement of serumprostate specific antigen (PSA) measurement are reviewed. Prostate cancer was diagnosed in 105 patients. PSA was found to be superior to prostatic acid phosphatase in the discrimination between prostate cancer and benign prostatic conditions. In 105 patients with newly diagnosed prostate cancer, scintigraphic evidence of osseous metastases was found in thirty-seven. No patients with a serum PSA value less than three times the upper normal limit of the assay had a positive bone scan. Isotope bone scan can be omitted in these patients, if they are not considered candidates for curative treatment.

Representations of graphomotor trajectories in the human parietal cortex: evidence for controlled processing and automatic performance.

The aim of this study was to identify the cerebral areas activated during kinematic processing of movement trajectories. We measured regional cerebral blood flow (rCBF) during learning, performance and imagery of right-hand writing in eight right-handed volunteers. Compared with viewing the writing space, increases in rCBF were observed in the left motor, premotor and frontomesial cortex, and in the right anterior cerebellum in all movement conditions, and the increases were related to mean tangential writing velocity. No rCBF increases occurred in these areas during imagery. Early learning of new ideomotor trajectories and deliberately exact writing of letters both induced rCBF increases in the cortex lining the right intraparietal sulcus. In contrast, during fast writing of overlearned trajectories and in the later phase of learning new ideograms the rCBF increased bilaterally in the posterior parietal cortex. Imagery of ideograms that had not been practised previously activated the anterior and posterior parietal areas simultaneously. Our results provide evidence suggesting that the kinematic representations of graphomotor trajectories are multiply represented in the human parietal cortex. It is concluded that different parietal subsystems may subserve attentive sensory movement control and whole-field visuospatial processing during automatic performance.

Dynamic scanning of 15O-butanol with positron emission tomography can identify regional cerebral activations.

To determine task-specific activations of the human brain in individual subjects, we applied pixel-by-pixel t-map statistics to the regional cerebral perfusion data obtained sequentially by dynamic scanning of [15O]-butanol with positron emission tomography (PET). The listmode data were binned into frames of 2 sec, and multiple corresponding pixel-by-pixel activation-minus-control subtractions were used for t-map calculation. The subtraction frames covering 10-40 sec after tracer arrival in the brain showed the activation-related increase of regional cerebral perfusion. A mismatch of the activation and control data by 2 sec resulted in a mean error of <5% of the integrated activity increase. To validate these results, we simulated images with a spatial resolution and signal-to-noise ratio equivalent to that of the [15O]-butanol subtraction images. By means of these simulated images, we determined the minimal data requirements for t-map analysis, the degree of spatial correlations in the image matrix, and the distribution of noise in the t-maps. The simulation results provided a measure to estimate the significance of regional cerebral perfusion changes recorded with [15O]-butanol. The location and spatial extent of regional cerebral activations obtained from dynamic data corresponded closely to those obtained with quantitative measurements of regional cerebral blood flow (rCBF). Our results show that statistical parametric mapping of [15O]-butanol scanning data allows the detection of significant, task-specific brain activations in single activation-control comparisons in individual subjects.

[Excess mortality of severely handicapped patients in mandatory health insurance]. / Ubersterblichkeit bei Schwerpflegefällen der gesetzlichen Krankenversicherung.

The introduction of compulsory long term care insurance as of 1.1. 1995 has temporarily brought to an end a whole range of controversial discussions, which have been strongly coloured by party political interests. The originally planned expenditure figure of at least DM 30 billion represents an enormous outlay in these time of economic recession. It is already abundantly clear that the premium payments will not be sufficient in the long run, nor will it be possible to increase these premiums arbitrarily. This therefore elicits the question as to whether it is possible to calculate in advance the cost of treatment for those "in serious need of nursing care" on the basis of various factors such as age, sex, underlying illness, therapy and social integration. Up to now, there has been very little statistical analysis of these parameters. For this reason, the company MDK has carried out a preliminary survey (which so far has only looked at a limited number of cases) in order to obtain a general idea of the variations in the period required for long term care. This survey has shown that there are two main groups of cases requiring care, which can be differently assessed on the basis of age and sex. On the one hand, there are those in serious need of nursing care, who, due to a life-threatening disease or as a result of an acute deterioration of an existing chronic condition (e.g. severe KHK, cirrhosis of the liver, decompensated renal insufficiency) die a relatively short time after the application for care is made.(ABSTRACT TRUNCATED AT 250 WORDS)