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.

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.

Individual integration of positron emission tomography and high-resolution magnetic resonance imaging.

We have developed, validated, and employed a technique of retrospective spatial alignment and integrated display of positron emission tomographic (PET) and high-resolution magnetic resonance (MR) brain images. The method was designed to improve the anatomical evaluation of functional images obtained from single subjects. In the first computational step, alignment of PET and MR data sets is achieved by iteratively matching in three orthogonal views the outermost scalp contours derived from front-to-back projections of each data set. This procedure avoids true three-dimensional modeling, runs without user interaction, and tolerates missing parts of the head circumference in the image volume, as usually the case with PET. Thereafter, high-resolution MR sections corresponding to the PET slices are reconstructed from the spatially transformed MR data. In a phantom study of this method, PET/MR alignment of the phantom's surface was accurate with average residual misfits of 2.17 to 2.32 mm as determined in three orthogonal planes. In-plane alignment of the phantom's insertion holes was accurate with an average residual misfit of 2.30 mm. In vivo application in six subjects allowed the individual anatomical localization of regional CBF (rCBF) responses obtained during unilateral manual exploration. In each subject, the maxima of the rCBF activations in the hand area were precisely allocated to gray matter in the anterior or posterior wall of the central sulcus. The configuration of the rCBF responses closely followed the gyral structures. The technique provided a better topographical understanding of rCBF changes in subtraction images of PET activation studies. It opens the perspective for studies of structural-functional relationships in individual subjects.

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.

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.

Large-scale plasticity of the human motor cortex.

The adult primate brain is capable of modifying rapidly the size of cortical receptive fields or motor output modules in response to altered synaptic input. We used positron emission tomography (PET) to map the regional cerebral blood flow changes related to voluntary finger movements in patients with tumours occupying the hand area of motor cortex. All patients showed activations solely outside the tumour. Compared with the unaffected side, the activations were shifted by 9-43 mm either along the mediolateral body representation of motor cortex or into premotor or parietal somatosensory cortex. These results provide evidence that slowly developing lesions can induce large-scale reorganization that is not confined to changes within the somatotopic body representation in motor cortex.

Successive roles of the cerebellum and premotor cortices in trajectorial learning.

The structures of the human brain engaged during learning of unilateral trajectorial hand movements were mapped by measurements of regional cerebral blood flow. Trajectorial movement velocity accelerated moderately after short-term training p < 0.025 and increased further after long-term training p < 0.01. During the early phase of learning there was a significant activation p < 0.001 of the ipsilateral dentate nucleus. By contrast, after overlearning the premotor cortical areas in both cerebral hemispheres were maximally activated p < 0.001, while the dentate nucleus was no longer activated. It is suggested that learning of new movement trajectories involves the cerebellum, while overlearned trajectorial movements engage the premotor cortex.

Cerebral hemodynamics during sensorimotor activation in humans.

We studied the time course and magnitude of cerebral blood flow velocity (CBFV) changes in the middle cerebral artery (MCA) and the regional cerebral blood flow (rCBF) in the MCA territory during stimulation of the left sensorimotor cortex. Healthy right-handed male subjects were examined during performance of right-hand finger movement sequences, vibratory stimulation, and somatosensory discrimination. In somatosensory discrimination there were significant increases of the mean CBFV (4.8 +/- 9.9 cm/s; P < 0.01) and the mean rCBF (10.2 +/- 4.2 ml.100 g-1.min-1; P < 0.01), whereas no significant changes of the mean CBFV and rCBF occurred in finger movement sequences or vibratory stimulation. During all stimulation sessions the mean CBFV changes increased rapidly and reached a first maximum 3.3 +/- 0.3 s after stimulation onset. Simultaneous measurements of relative mean CBFV changes in both MCAs revealed left-right differences during voluntary finger movement sequences (left MCA, 14.3 +/- 10.6%; right MCA, 0.9 +/- 11.6%; P < 0.001) corresponding to a higher mean rCBF change in the left MCA territory. In the two tasks involving finger movements there was an increase of the respiratory rates (4.3 +/- 3.8 breaths/min; P < 0.05) and the pulse rates (11.6 +/- 5.5 beats/min; P < 0.05), respectively. Our data demonstrate a correspondence of mean CBFV and rCBF changes evoked by sensorimotor activation in the human brain. Furthermore, cerebral hemodynamic changes related to motor activity are accompanied by cardiorespiratory effects.

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.

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.

[A panorama of rheumatic diseases]. / Das Panorama des rheumatischen Formenkreises.

The developments in our health care system mean that the significance of chronic, cost-intensive diseases is continually increasing in terms of diagnosis, treatment and prevention. Under this aspect, rheumatic diseases may be regarded as prime examples in that they generate expenditure in many areas of both social insurance and private insurance. Although many of the disorders classified as rheumatic diseases manifest themselves clinically in the form of complaints in the region of the skeletal system, it should not be forgotten that they are actually systemic disorders, i.e. they have immunological or metabolic causes. This aspect plays a significant role with regard to the possibility of long-term prognosis and hence with regard to life expectancy as well. It also exerts a major influence on the selection of therapeutic concepts which are hoped to slow down the progress of a disease or stop it altogether. Precise inquiries, careful diagnosis, patient-specific therapy, and not least growing health consciousness should be capable of exerting a positive influence on the course of even relatively severe rheumatic conditions. The consequences will be felt to a corresponding degree by the private insurers too.

[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)

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.

Inter-subject variability of cerebral activations in acquiring a motor skill: a study with positron emission tomography.

Cerebral structures activated during sequential right-hand finger movements were mapped with regional cerebral blood flow (rCBF) measurements by positron emission tomography (PET) in individual subjects. Nine healthy volunteers were examined twice; after initial learning and after practicing the finger movement sequence for more than 1 h. Task-specific activation sites were identified by statistical distributions of maximal activity and region size in rCBF subtraction images. A consistent task-specific activation in all nine subjects was detected in the contralateral sensorimotor cortex at an average movement rate of 3.2 Hz reached after practice. This corresponded to a significant increase of the mean rCBF in the left primary sensorimotor cortex in spatially standardised and averaged PET images. Additional task-specific activation sites detected by individual analysis were found in the lateral and medial premotor, parietal, and cingulate areas, and in subcortical structures including the basal ganglia of both cerebral hemispheres. These activations showed no or little spatial overlap from subject to subject, thus being obscured in the analysis of pooled data. The observed activity patterns were related to movement rate and accuracy in individual subjects. It is suggested that the rCBF changes associated with acquisition of a motor skill in individual humans may correspond to plasticity of sensorimotor representations reported in monkeys.

A neuromagnetic study of the functional organization of the sensorimotor cortex.

Movement-related neuromagnetic fields from eight healthy human subjects were investigated in a Bereitschaftspotential paradigm. The three conditions studied were right-sided mouth, index finger and foot movement. The neuromagnetic field patterns corresponding to the motor field and the movement-evoked field I were analysed using a moving dipole model. For both components a somatotopic organization was found: the estimated dipole locations for the mouth were more lateral and those for the foot more medial than the estimated dipole positions for the index finger movement. With regard to possible clinical applications, e.g. non-invasive mapping of the sensorimotor cortex and studies of plasticity of the motor function, the present results suggest that the investigation of movement-evoked field I for the index finger condition is most likely to yield further results.