Time perception in patients with major depressive disorder during vagus nerve stimulation.

BACKGROUND: Affective disorders may affect patients' time perception. Several studies have described time as a function of the frontal lobe. The activating eff ects of vagus nerve stimulation on the frontal lobe might also modulate time perception in patients with major depressive disorder (MDD). METHODS: Time perception was investigated in 30 patients with MDD and in 7 patients with therapy-resistant MDD. In these 7 patients, a VNS system was implanted and time perception was assessed before and during stimulation. A time estimation task in which patients were asked "How many seconds have passed?" tested time perception at 4 defined time points (34 s, 77 s, 192 s and 230 s). The differences between the estimated and actual durations were calculated and used for subsequent analysis. RESULTS: Patients with MDD and healthy controls estimated the set time points relatively accurately. A general linear model revealed a significant main eff ect of group but not of age or sex. The passing of time was perceived as significantly slower in patients undergoing VNS compared to patients with MDD at all time points (T34: t = − 4.2; df = 35; p < 0.001; T77: t = − 4.8; df = 35; p < 0.001; T192: t = − 2.0; df = 35; p = 0.059; T230 t = −2.2; df = 35; p = 0.039) as well as compared to healthy controls (at only T77: t = 4.1; df = 35; p < 0.001). There were no differences in time perception with regard to age, sex or polarity of depression (uni- or bipolar). CONCLUSIONS: VNS is capable of changing the perception of time. This discovery furthers the basic research on circadian rhythms in patients with psychiatric disorders.

Changes in gustatory perceptions of patients with major depression treated with vagus nerve stimulation (VNS).

BACKGROUND: Olfactory and gustatory functions were investigated before and during vagus nerve stimulation (VNS) in a group of 9 patients with therapy-resistant depression, implanted with a VNS system. METHODS: Gustation and olfaction were tested using standard sniffing tests. Subjects participated in 2 sessions with the vagal stimulator switched on and off, respectively. RESULTS: Under conditions of stimulation of the VNS, there were statistically significant differences of the threshold of perception, with an intensification of the taste "sweet" (Z = -2.0; p = 0.048) and "bitter" (Z = - 2.5; p = 0.011) compared to the "off-mode". A statistical trend (Z = - 1.7; p=0.098) for increased intensity of the taste "salty" was observed, however, these results would supposedly disappear after correction for multiple testing presumably due to the large number of variables and the small sample size. There were no statistically relevant differences concerning olfactory perception. CONCLUSIONS: The changes of gustatory perception under conditions of vagal nerve stimulation observed in this study show another important central nervous effect of vagal stimulation on the limbic system that might be of importance in the elucidation of mechanisms of action of VNS especially on refractory depression.

Cardiac effects of vagus nerve stimulation in patients with major depression.

INTRODUCTION: Changes in the heart rate variability are well known among patients with depression. Amongst others, a modulation of the autonomic nervous system is discussed. An investigation of heart rate variability during terms of stimulation could give some insight in the central nervous effect of vagus nerve stimulation (VNS) and possible cardiac side effects. METHODS: The effects of VNS on heart rate (HR) and heart rate variability were studied (HRV) during stimulation in nine patients with major depression according to ICD-10. RESULTS: When comparing treated depressive patients with a sex- and age-matched healthy control group, the analysis of heart rate revealed significantly (t=2.8; df=16, p=0.012) elevated heart rates during completely switched off conditions, during switched on VNS programme in stimulation-free intervals (5 min period) (t=3.0; p=0.009) and during stimulation conditions (30 s) (t=2.8, Levene corrected, p=0.015). The RMSSD (root mean square of successive differences) as a measure of the HRV increased significantly in switched on conditions during stimulation (30 s) in six patients compared to stimulation-free intervals (t=-4.7; df=5, p=0.006) and baseline. DISCUSSION: Clinically relevant cardiac effects were not observed throughout the study. VNS induces reversible changes in heart rate variability in patients with major depression during stimulation conditions.

[An exploration of the association between disability pension and psychiatric diseases]. / Frühberentung aufgrund psychiatrischer Erkrankungen. Eine Analyse von 94 Berufsunfähigkeitsgutachten.

OBJECTIVE: The necessity to establish disability and invalidity pensions due to psychiatric diseases has become more and more demanding in recent years. So far there is little knowledge about the aetiology and socio-demographic aspects of this phenomenon. METHODS: The presented explorative analyses included 94 examinations (43 women, 51 men) to address, if a person should be medically certified as partly or permanently unfit for work. The data, including psychiatric diagnosis and socio-demographic data were obtained between 1999 and 2006 in a German specialised psychiatric university unit. RESULTS: The diagnoses of neurotic diseases, stress related and somatoform disorders (ICD-10 F 40 - 48) were the most prevalent group (48 %) within the sample. It was a statistically significant predictive factor in a later declaration of disability and invalidity. In this diagnosis group (F 40 - 48) more participants were female when compared to other diagnosis groups. In general, participants were more likely to be divorced and have a lower education level when compared to the general population. However, the mean level of intelligence was similar to the general population. CONCLUSION: The results of the presented study could be beneficial for a better understanding of the association between disability pensions and psychiatric diseases. The increase of neurotic diseases, stress related and somatoform disorders may justify the development of targeted prevention strategies.

[Long-term analysis of disability pensions in survivors of the Holocaust: somatic and psychiatric diagnoses]. / Erwerbsminderung bei Holocaustopfern: eine langzeitkatamnestische Betrachtung somatischer und psychiatrischer Diagnosen unter Berücksichtigung des Gesamtschauaspekts.

OBJECTIVE: Survivors of the Holocaust are known to suffer more often from mental as well as somatic consequential illness. The assessment of the degree of disability and invalidity due to the persecution complies with the interaction of directly Holocaust-related mental and somatic primary injuries as well as physical, psychical and psychosocial disadvantages and illnesses acquired later on. METHODS: The presented descriptive as well as multivariate analyses included complete reports (expertise, medical records, physicians' assessments, witnessed hand-written notes of the patients) of 56 survivors of the Holocaust (36 women and 20 men). RESULTS: The disability pension reports of 56 Holocaust survivors (36 women and 20 men) were analysed referring to the diagnostic groups and socio-demographic aspects. In 92.3 % a psychiatric illness could be diagnosed within the first year after liberation. In a separate analysis of somatic diagnoses, gastrointestinal diseases were statistically significant more often in Holocaust survivors with a degree of disability of more than 30 % (chi-square χ (2) = 4.0; df = 1; p = 0.046). CONCLUSIONS: The question of an aggravation of psychiatrically relevant and persecution-associated symptomatology is mainly the objective of the expert opinion taking into account endogenous and exogenous factors such as so-called life events. Above all, newly acquired somatic diseases seem to be responsible for an aggravation of persecution-associated psychiatric symptoms, at least in the presented sample of Holocaust survivors.

Clinical benefits and cost effectiveness of vagus nerve stimulation in a long-term treatment of patients with major depression.

BACKGROUND: To evaluate clinical aspects and cost effectiveness of the treatment with vagus nerve stimulation (VNS), a group of 9 VNS-implanted patients and 9 age- and sex-matched patients suffering from treatment-resistant depression were included in a prospective study. METHODS: The psychopathological ratings over 12 months as well as socio-economic data on the duration of hospitalisation, frequency of outpatient treatment, and subsequent drug treatment were compared with the pre-implantation period. RESULTS: Compared with baseline values in the HAMD scale (mean 23.7; SD 2.4), there was a significant (t=14.5; df=8; p<0.001) improvement in symptoms after 12 months' stimulation (mean 10.2; SD 2.4). The duration of hospitalisation dropped on average by 20 days in the first post-implantation year, the treatment frequency from 33 to 14 visits, and drug treatment from 4 to an average of 3 psychotropic drugs. CONCLUSION: In addition to an improvement in clinical symptoms, the VNS method might enable an amortisation of costs.

Spontaneous slow and fast MEG activity in male schizophrenics treated with clozapine.

RATIONALE: The atypical neuroleptic clozapine induces specific electroencephalogram changes, which have not been investigated using the technique of magnetoencephalography (MEG). OBJECTIVE: The present study investigated whether spontaneous magnetoencephalographic (MEG) activity in patients treated with clozapine differs from that in patients treated with haloperidol and untreated control subjects. METHODS: A 2 x 37 channel biomagnetic system was used to record spontaneous magnetic activity for the frequency ranges (2-6 Hz), (7.5-12 Hz), (12.5-30 Hz) in schizophrenic patients and controls in two trials within 3 weeks. After data acquisition, the processed data were digitally filtered and the spatial distribution of dipoles was determined by a 3-D convolution with a Gaussian envelope. The dipole localisation was calculated by the dipole density plot and the principal component analysis. The target parameters were absolute dipole values and the dipole localisations. The relationship between absolute dipole values, dipole localisations and psychopathological findings (documented by the use of the PANSS, BPRS-scale) during a 3 week period with constant doses of clozapine and haloperidol was investigated using correlation analysis. RESULTS: Our results lend strong support to the assumption of a significant elevation of absolute dipole values [dipole density maximum (Dmax), dipole number (Dtotal), absolute and relative dipole density] in the fast frequency range (12.5-30 Hz) over the left hemisphere, especially in the temporoparietal region by clozapine. In this area, we found a dipole concentration effect only in patients treated with the atypical neuroleptic, whereas the dipole distribution in patients treated with haloperidol and healthy controls was concentrated in the central region. With regard to the absolute dipole values in the frequency ranges 2-6 Hz (delta, theta) and 7.5-12 Hz (alpha), we found no statistically significant differences between the groups investigated. In the slow frequency range (2-6 Hz) no difference was found between the clozapine and haloperidol group for the dipole localisation, which predominated in the temporoparietal region, in contrast to the central dipole distribution in control subjects. CONCLUSIONS: The results of an increase in beta activity under clozapine demonstrate a smaller reduction in activity in terms of unspecific sensory and motor paradigms in comparison with typical neuroleptics. The temporoparietal concentration of dipoles, in particular over the left half of the brain, might illustrate either their special role in the disease process, or the effects of the medication. The latter possibility was supported by the differing dipole distribution in the clozapine group with a left temporoparietal centre in both frequency ranges, and a deviating central dipole localisation in the fast activity range in the haloperidol group.

Spontaneous, slow and fast magnetoencephalographic activity in patients with schizophrenia.

A 2* 37 channel biomagnetic system (Magnes II) was used to record spontaneous magnetic activity for the frequency ranges 2-6 Hz and 12.5-30 Hz in 30 patients with schizophrenia (23 men and 17 women) and 30 healthy volunteers in both hemispheres during a resting condition. The dipole localization was calculated by the dipole density plot (DDP) method, which is a spatial averaging in order to decrease the influence of the nonfocal activity. The quantified DDP results were superimposed to T2-weighted MR-images of each patient's head as isocontour lines. To superimpose the MEG results to 3-D MRI data, the scanned head data set was fitted to the reconstructed MRI head shape using a surface fit programme developed by our department. The absolute dipole values were correlated with the psychopathological findings and the cumulative neuroleptic dosage for each patient. The group of patients with schizophrenia differed overall from the healthy subjects in the elevation of absolute dipole values measured in both hemispheres. For the region of slow dipole activity (2-6 Hz), a high correlation was found between the intensity of dipole concentration and productive psychotic symptoms (PANSS, P1-P7). Dipole localization (for both frequency ranges) showed a concentration effect (DCE) in the temporoparietal region in patients with schizophrenia.

Risk assessment of alcohol withdrawal seizures with a Kohonen feature map.

Recently, it has been suggested that alcohol-induced hyperhomocysteinaemia in patients suffering from chronic alcoholism might be a risk factor for alcohol withdrawal seizures. In the present follow-up study 12 patients with chronic alcoholism who suffered from withdrawal seizures had significantly higher levels of homocysteine (Hcy) on admission (71.43 +/- 25.84 mol/l) than patients (n = 37) who did not develop seizures (32.60 +/- 24.87 mol/l; U = 37.50, p = 0.0003). Using a logistic regression analysis, withdrawal seizures were best predicted by a high Hcy level on admission (p < 0.01; odds ratio 2.07). Based on these findings we developed an artificial neural network system (Kohonen feature map, KFM) for an improved prediction of the risk of alcohol withdrawal seizures. Forty-nine patients with chronic alcoholism (12 with alcohol withdrawal seizures and 37 without seizures) were randomized into a training set and a test set. Best results for sensitivity of the KFM was 83.3% (five of six seizure patients were predicted correctly) with a specificity of 94.4% (one false positive prediction of 19 patients). We conclude that in patients with alcohol-induced hyperhomocysteinaemia the KFM is a useful tool to predict alcohol withdrawal seizures.

Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.

Chronic alcohol consumption can induce brain atrophy, whereby the exact mechanism of brain damage in alcoholics remains unknown. There is evidence that chronic alcoholism is associated with hyperhomocysteinemia. Homocysteine is an excitatory amino acid which markedly enhances the vulnerability of neuronal cells to excitotoxic and oxidative injury in vitro and in vivo. The present volumetric magnetic resonance imaging study included 52 chronic alcoholics and 30 non-drinking healthy controls. Patients were active drinkers and had an established diagnosis of alcohol dependence. We investigated the influence of different variables on the hippocampal volume of patients suffering from chronic alcoholism. We observed that pathological raised levels of plasma homocysteine showed the most significant correlation to hippocampal volume reduction (P<0.001, multiple regression analysis). Raised plasma levels of homocysteine are associated with hippocampal (brain) atrophy in alcoholism.

Evaluation of neuronal effects of electroconvulsive therapy by magnetoencephalography (MEG).

1. Interictal spontaneous MEG was investigated in five male patients with major depressive disorder (according to DSM IV) treated with right hemispheric ECT over a period of five weeks. Spontaneous MEG-activity was also recorded in five male patients treated with tricyclic antidepressants during the same time period. 2. The analysis of slow (0-7Hz) and fast (12.5-30Hz) MEG activity was done with the dipole density plot, which uses consecutively estimated dipoles across a given analyzing time and delivers quantified dipole concentrations in three dimensions 3. In the ECT group the authors found a significant increase in the dipole concentration in the slow activity range (0-7Hz) after the first and the subsequent treatments, which could not be found in patients treated with tricyclic antidepressants. The localisation of the dipoles showed an "anteriorposterior"--gradient with a maximum concentration in the frontal and temporal region. 4. In the fast activity range (12.5-30Hz) the ECT group differed from the control group by a significant decrease of dipole activity, which was concentrated in the temporal and parietal region. 5. These results in part confirm interictal EEG findings after right hemispheric ECT and also lend strong support to ECT-effects in the fast activity ranges.

The reduction of alcohol consumption with novel pharmacological intervention.

The development of pharmacological agents in treating alcoholism represents one of many different ways to suppress alcohol intake. Regarding the hypothetical involvement of different neurochemical systems in "alcohol craving", specific substances have been examined in animals models (especially rats) and increasingly in man. Promising results in reducing "alcohol craving" were described in the use of different kinds of chemical substances. "Craving" therefore can hardly be explained on the basis of a deficit in only one neurochemical (neurotransmitter) system. This conclusion is supported by the data. The efficiacy of many anti-craving substances described in smaller studies must first be confirmed in clinical studies on a wider scale.

Global panic reaction II - a 7-step repetitive vicious circle.

The GPR-II model describes a "7-step" panic model. In this model, the single panic patient is not only affected as single member. The pressure weighing on him is not only exerted by external factors but also by group members of his network. Therefore, he has to cope with his individual problems and with the expectations of all members. The "therapeutic" model of instant sedation used (rescue screens) and long-lasting steps (behavioural therapy in group models) are not appropriate to treat the patients successfully.

Why not "double schizophrenia"?

The current approach to schizophrenic psychoses comprises the concept of a course characterized by a prodromal phase, an intermittent acute phase, and residual formation. Similar to the concept of the so-called double depression, there are, in addition to the subgroups of patients with primarily cognitive changes, patients in whom neurotic-dissociative components dominate prior to the disease outbreak itself. The question arises whether this process, considered thus far as prodromal, may possibly be interpreted beyond this as a combined pattern of progression in the sense of a "double schizophrenia" and thus differ symptomatically in the further course from other forms of schizophrenia. If so, in addition to the usual neuroleptic treatment, therapy should include an additional focus with more psychotherapeutic attention.

Nucleus lentiformis--a new model for psychiatry?

In a regions of interest analysis (ROI) of the most frequent psychiatric disorders (schizophrenia, depression, anxiety, addiction), we found the nucleus lentiformis to be the topographical brain region most frequently cited in connection with these disorders in a regions of interest survey of publications between 1990-2010. This structure, which controls particularly motorics, appears to have a much greater importance than has thus far been assumed in the control and modulation of psychiatric disorders. The question of the extent to which this region has its own control function with respect to the disorders should be addressed in further studies along with clarification of possible influence factors on the activity.

A functional magnetic resonance imaging navigated repetitive transcranial magnetic stimulation study of the posterior parietal cortex in normal pain and hyperalgesia.

Noxious stimuli activate a complex cerebral network. During central sensitization to pain, activity in most of these areas is changed. One of these areas is the posterior parietal cortex (PPC). The role of the PPC during processing of acute pain as well as hyperalgesia and tactile allodynia remains elusive. Therefore, we performed a functional magnetic resonance imaging (fMRI) based, neuro-navigated, repetitive transcranial magnetic stimulation (rTMS) study in 10 healthy volunteers. Firstly, pin-prick hyperalgesia was provoked on the right volar forearm, using the model of electrically-induced secondary mechanical hyperalgesia. fMRI was performed during pin-prick stimulation inside and outside the hyperalgesic areas. Secondly, on four different experimental sessions, the left and right individual intraparietal BOLD peak-activations were used as targets for a sham-controlled 1 Hz rTMS paradigm of 10 min duration. We measured psychophysically the (i) electrical pain stimulus intensity on an 11-point numeric pain rating scale (NRS, 0-10), the (ii) area of hyperalgesia, and the (iii) area of dynamic mechanical allodynia. Sham stimulation or rTMS was performed 16 min after induction of pin-prick hyperalgesia and tactile allodynia. Compared to sham stimulation, no significant effect of rTMS was observed on pain stimulus intensity and the area of allodynia. However, a reduction of the hyperalgesic area was observed for rTMS of the left PPC (P<0.05). We discuss the role of the PPC in central sensitization to pain, in spatial discrimination of pain stimuli and in spatial-attention to pain stimuli.