Factors associated with dropout in the longitudinal Vogel study of cognitive decline.

Dementia, including Alzheimer's disease, is a growing problem worldwide. Prevention or early detection of the disease or a prodromal cognitive decline is necessary. By means of our long-term follow-up 'Vogel study', we aim to predict the pathological cognitive decline of a German cohort (mean age was 73.9 ± 1.55 years at first visit) with three measurement time points within 6 years per participant. Especially in samples of the elderly and subjects with chronic or co-morbid diseases, dropouts are one of the biggest problems of long-term studies. In contrast to the large number of research articles conducted on the course of dementia, little research has been done on the completion of treatment. To ensure unbiased and reliable predictors of cognitive decline from study completers, our objective was to determine predictors of dropout. We conducted multivariate analyses of covariance and multinomial logistic regression analyses to compare and predict the subject's dropout behaviour at the second visit 3 years after baseline (full participation, partial participation and no participation/dropout) with neuropsychiatric, cognitive, blood and lifestyle variables. Lower performance in declarative memory, attention and visual-spatial processing predicted dropout rather than full participation. Lower performance in visual-spatial processing predicted partial participation as opposed to full participation. Furthermore, lower performance in mini-mental status examination predicted whether subjects dropped out or participated partially instead of full participation. Baseline cognitive parameters are associated with dropouts at follow-up with a loss of impaired participants. We expect a bias into a healthier sample over time.

Near-infrared spectroscopy (NIRS) and vagus somatosensory evoked potentials (VSEP) in the early diagnosis of Alzheimer's disease: rationale, design, methods, and first baseline data of the Vogel study.

Functional near-infrared spectroscopy (fNIRS) and vagus somatosensory evoked potentials (VSEP) show deviant patterns in subjects with Alzheimer's disease (AD) compared to healthy controls. We now aimed at testing the predictive value of these methods in the early diagnosis of AD. The Vogel study is a prospective, observational, long-term follow-up study with three time points of investigation within 6 years. Residents of the city of Würzburg born between 1936 and 1941 were recruited. Every participant underwent physical, psychiatric, and laboratory examinations, and performed an intense neuropsychological testing as well as VSEP and NIRS according to the published procedures. 604 subjects were included. Mean age of the participants was 73.9 ± 1.55 years. The most frequent pathological physical and laboratory examination results were observed for blood pressure (62%), body weight (54%), HbA1c (16%), cholesterol (42%), and homocysteine (69%). Comprehensive analysis of cognitive testing showed mild cognitive impairment (MCI) in 12.3% of the patients. Concurrent major depression was found in 6.6% of the patients. We observed a high rate of MCI and somatic comorbidity in our cohort. The high rate of vascular risk factors and depressive symptoms, all of which are known risk factors of AD, is consistent with the notion that there are multiple options to prevent or postpone the onset of AD in a geriatric population like the one of the Vogel studies.

Transcranial direct current stimulation of the prefrontal cortex increases attention to visual target stimuli.

Both functional imaging or EEG studies and studies including neurological patients found the dorsolateral prefrontal cortex (dLPFC) to be an important brain area for the processing of emotion and attention. The aim of the present study was to investigate whether emotion and attention can be modulated through bilateral transcranial direct current stimulation (tDCS) of the dLPFC. Therefore, we measured electroencephalographic occipital (early posterior negativity, EPN) and parietal ERPs (late positive potential, LPP) during an emotional picture viewing paradigm with an additional attentional instruction while applying bilateral anodal and cathodal tDC-stimulation to the left and right dLPFC. Beyond the well-known emotion and attention effects for both EPN and LPP, we found that left cathodal/right anodal tDCS leads to increased LPP amplitudes to target stimuli. In contrast to our hypothesis bilateral tDCS over the dLPFC did not influence emotional processing.

Transcranial direct current stimulation of the prefrontal cortex reduces cue-reactivity in alcohol-dependent patients.

Alcohol craving has been shown to be an important factor for relapses in alcohol-dependent patients. Furthermore, brain activity in reward-related areas in response to alcohol-related cues is positively related to the amount of post-relapse alcohol consumption. On the other hand, it has been shown that cue-exposure based extinction training (CET) leads to larger decrease of striatal and left dorsolateral prefrontal cortex (dLPFC) cue-induced activation compared to standard clinical day-care treatment, but the effect sizes are relatively small. The question of this study was, whether it is possible to change cue-reactivity and subjective craving by applying bilateral prefrontal transcranial direct current stimulation (tDCS). We stimulated 30 detoxified alcohol-dependent patients (50 % with a sham and 50 % with left cathodal/right anodal stimulation) and presented emotional as well as alcohol-related pictures. We measured the emotional startle modulation and found significantly increased startle amplitudes in the verum stimulation condition for alcohol-related cues, indicating a more negative processing of this cues in alcohol-dependent patients after verum tDCS stimulation. Additionally we found tendencies for stronger reduction in subjective craving in verum-stimulated patients. Therefore our study underscores the positive value of DCS in reducing craving and might help to improve the understanding and therapy of alcohol dependence.

Vagus somatosensory evoked potentials are delayed in Alzheimer's disease, but not in major depression.

In Alzheimer's disease (AD), the degeneration of brainstem nuclei is different from major depression (MD). Thus, vagus somatosensory evoked potentials (VSEP) proposed for the functional assessment of brainstem nuclei should show prolonged latencies in AD but not in MD. In 55 AD patients, 57 MD patients and two age-matched control groups evoked potentials were recorded upon stimulation of the auricular branch of the vagus nerve. In the AD, not in the MD group, latencies were significantly longer as compared to controls. Thus, the method of VSEP could contribute to the important differential diagnosis of AD and MD in elderly patients.

Prefrontal correlates of approach preferences for alcohol stimuli in alcohol dependence.

An approach bias for alcohol stimuli (i.e. faster approach than avoidance reactions) might facilitate relapses in alcohol dependence. Neurobiological models suggest hypersensitivity in the reward system [inter alia nucleus accumbens and orbitofrontal cortex (OFC)] to cause pathologically enhanced approach impulses towards alcohol stimuli. At the same time, in alcohol dependence, these structures are only insufficiently controlled by a hypoactive dorsolateral prefrontal cortex (DLPFC). The present study investigated the cortical aspects of this model with functional near-infrared spectroscopy in 21 alcohol-dependent in-patients and 21 healthy controls (HC; comparable in age, gender and education) during performance of the Approach-Avoidance Task (AAT) for the first time. Complementing previous findings, in reaction times (RTs), patients showed stronger approach preferences for alcohol than non-alcohol stimuli. For non-alcohol stimuli, patients even displayed avoidance preferences. The reversed pattern was found in HC. Group differences in activity of the OFC were identical to those in RTs, revealing patients to assign higher subjective value to approaching alcohol stimuli. In both groups, regulatory activity in the right DLPFC was stronger during avoiding than approaching alcohol pictures. Probable awareness of the behavioural hypotheses due to explicit task instructions and patients' deficient prefrontal function might account for this equally aligned pattern. Results are discussed with regard to recent findings revealing a reduced behavioural approach bias and risk for relapse by applying a retraining version of the AAT. Functional measurements might serve as a method for monitoring the corresponding neurobiological changes and-possibly-predicting the success of such a training.

Functional near-infrared spectroscopy to probe state- and trait-like conditions in chronic tinnitus: a proof-of-principle study.

OBJECTIVE: Several neuroscience tools showed the involvement of auditory cortex in chronic tinnitus. In this proof-of-principle study we probed the capability of functional near-infrared spectroscopy (fNIRS) for the measurement of brain oxygenation in auditory cortex in dependence from chronic tinnitus and from intervention with transcranial magnetic stimulation. METHODS: Twenty-three patients received continuous theta burst stimulation over the left primary auditory cortex in a randomized sham-controlled neuronavigated trial (verum = 12; placebo = 11). Before and after treatment, sound-evoked brain oxygenation in temporal areas was measured with fNIRS. Brain oxygenation was measured once in healthy controls (n = 12). RESULTS: Sound-evoked activity in right temporal areas was increased in the patients in contrast to healthy controls. Left-sided temporal activity under the stimulated area changed over the course of the trial; high baseline oxygenation was reduced and vice versa. CONCLUSIONS: By demonstrating that rTMS interacts with auditory evoked brain activity, our results confirm earlier electrophysiological findings and indicate the sensitivity of fNIRS for detecting rTMS induced changes in brain activity. Moreover, our findings of trait- and state-related oxygenation changes indicate the potential of fNIRS for the investigation of tinnitus pathophysiology and treatment response.

Intermittent theta burst stimulation of the left dorsolateral prefrontal cortex has no additional effect on the efficacy of virtual reality exposure therapy for acrophobia. A randomized double-blind placebo-controlled study.

Anxiety disorders are among the most common mental disorders. Treatment guidelines recommend pharmacotherapy and cognitive behavioral therapy as standard treatment. Although cognitive behavioral therapy is an effective therapeutic approach, not all patients benefit sufficiently from it. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, have been investigated as promising adjuncts in the treatment of affective disorders. The aim of this study is to investigate whether a combination of intermittent theta burst stimulation (iTBS) and virtual reality exposure therapy leads to a significantly greater reduction in acrophobia than virtual reality exposure with sham stimulation. In this randomized double-blind placebo-controlled study, 43 participants with acrophobia received verum or sham iTBS over the left dorsolateral prefrontal cortex prior to two sessions of virtual reality exposure therapy. Stimulation of the left dorsolateral prefrontal cortex with iTBS was motivated by an experimental study showing a positive effect on extinction memory retention. Acrophobic symptoms were assessed using questionnaires and two behavioral approach tasks one week before, after treatment and six months after the second diagnostic session. The results showed that two sessions of virtual reality exposure therapy led to a significant reduction in acrophobic symptoms, with an overall remission rate of 79 %. However, there was no additional effect of iTBS of the left dorsolateral prefrontal cortex on the therapeutic effects. Further research is needed to determine how exactly a combination of transcranial magnetic stimulation and exposure therapy should be designed to enhance efficacy.

Quetiapine and flupentixol differentially improve anterior cingulate cortex function in schizophrenia patients: an event-related potential study.

Atypical antipsychotic agents are a frequently and effectively used treatment in schizophrenia and psychotic disorders. Other than conventional antipsychotics, which mainly exert their pharmacological effect in subcortical dopaminergic systems, atypical antipsychotics additionally affect partly serotonergically innervated structures within prefrontal areas, such as the anterior cingulate cortex (ACC). However, only few controlled, randomized studies have so far investigated direct and indirect effects of atypical antipsychotics on the ACC and, up until now, no clinical investigation has exclusively addressed the specific effects of quetiapine on ACC function. The present study assessed ACC function in 18 quetiapine-medicated patients and 13 flupentixol-treated patients suffering from schizophrenia by means of the error-related negativity (ERN), a neurophysiological marker of ACC function, in a pre-post design. Between-group comparisons revealed different effects of quetiapine and flupentixol on ACC function despite similar improvement in psychopathology, cognitive performance and quality of life. Whereas atypical treatment was associated with an increase in amplitudes over time, there were prolonged ERN peak latencies in patients treated with the typical agent. Moreover, treatment effects depended on baseline prefrontal cortex function in both groups. We conclude that both flupentixol and quetiapine improve prefrontal function especially in patients with weak initial ACC function which might be due to their shared affinity for serotonin receptors in frontal brain regions. However, since this affinity is more pronounced for quetiapine, patients treated with quetiapine seemed to profit more evidently concerning their prefrontal cortex function compared to patients of the flupentixol group, who exhibited a compensatory prolongation of processes.

Is there a negative interpretation bias in depressed patients? An affective startle modulation study.

BACKGROUND/AIMS: Scientists proposed that patients with depression favour negative interpretations when appraising ambiguity. As self-report measures seem prone to response bias, implicit measures of emotional valence should be additionally used. METHODS: A total of 16 patients with depression and 19 controls underwent an acoustic imagery task comprising neutral and negative words, as well as ambiguous words that could be understood either way. Affective startle modulation and direct interrogation were used to assess implicit and explicit emotional valence, respectively. We expected a negative bias for ambiguous words in the patient group, resulting in augmented startle magnitudes and preference for negative interpretations of the ambiguous words in the interrogation. RESULTS: Surprisingly, both groups preferred neutral interpretations and showed augmented startle magnitudes to ambiguous words. Furthermore, both groups displayed an emotional startle potentiation for negative words. CONCLUSION: In summary, our results do not confirm a negative interpretation bias or a blunted emotional response in patients with major depression. The mismatch between self-report and affective startle reaction to ambiguous targets might reflect defensive mobilization or attention effects.

Vagus somatosensory evoked potentials--a possibility for diagnostic improvement in patients with mild cognitive impairment?.

OBJECTIVE: Vagus somatosensory evoked potentials (VSEP) are far-field potentials probably generated in nuclei of then. vagus in the lower brainstem. They represent a putative, easily applicable method for discrimination between patients with Alzheimer's disease (AD), patients with mild cognitive impairment (MCI), and healthy controls (HC). METHODS: Thirteen patients with AD, 12 with MCI, and 27 age- and gender-matched HC were investigated by stimulating the cutaneous branch of the n. vagus; 8, 6, and 20, respectively, were included in the main part of the analysis. RESULTS: In fronto-central recordings (electrode positions Fz-F4) a grading from HC over MCI to AD could be found, with a significant linear trend over the three groups and significantly increased latencies of the cognitively impaired patients but no significant difference between MCI and AD. CONCLUSION: The results indicate that the method of VSEP is able to discriminate between cognitively declined patients and HC, whereas no clear-cut differences were detected between MCI and AD.

Reduced parietal activation in participants with mild cognitive impairments during visual-spatial processing measured with functional near-infrared spectroscopy.

Functional Near Infrared Spectroscopy (fNIRS) may be a suitable, simple, and cost-effective brain imaging technique for detecting divergent neuronal patterns at an early stage of neurodegeneration. In course of Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD), a deficit in visual-spatial processing, located in the parietal cortex, is a reliable risk factor. Earlier, we established the application of the clock-hand-angle-discrimination task (ADT) during fNIRS to identify neuronal correlates of the visual-spatial processing in a healthy elderly sample. In this analysis, we aimed to measure and find out differences in the hemodynamic response in MCI participants compared to matched healthy controls. As expected, MCI participants showed more errors over all conditions of pointer length and a higher reaction time in the long and middle pointer length condition. Moreover, results revealed a significant reduction of cortical activation in MCI patients. There was a generally increased activity in both the right as compared to the left hemisphere and the superior parietal brain region as compared to the inferior parietal brain region in both groups. In summary, fNIRS can be implemented in the measurement of visual-spatial processing in MCI patients and healthy elderly based on ADT. MCI participants had difficulties to cope with the ADT. Since neuronal hypoactivity occurs with concomitant behavioral deficits, an additional analysis was performed on a subgroup of MCI patients who performed as well as the control group in behavior. This subgroup analysis also showed a hypoactivation of the parietal cortex, without evidence of a compensatory activation. Therefore, we assume that MCI patients are characterized by a deficit in the parietal cortex. Overall, these findings confirm our hypothesis that hemodynamic deficits in visual-spatial processing, localized in the parietal cortex, are reliable and early diagnostic markers for cognitive decline in risk groups for the development of AD.

Measurement invariance testing of longitudinal neuropsychiatric test scores distinguishes pathological from normative cognitive decline and highlights its potential in early detection research.

OBJECTIVE: Alzheimer's disease (AD) is a growing challenge worldwide, which is why the search for early-onset predictors must be focused as soon as possible. Longitudinal studies that investigate courses of neuropsychological and other variables screen for such predictors correlated to mild cognitive impairment (MCI). However, one often neglected issue in analyses of such studies is measurement invariance (MI), which is often assumed but not tested for. This study uses the absence of MI (non-MI) and latent factor scores instead of composite variables to assess properties of cognitive domains, compensation mechanisms, and their predictability to establish a method for a more comprehensive understanding of pathological cognitive decline. METHODS: An exploratory factor analysis (EFA) and a set of increasingly restricted confirmatory factor analyses (CFAs) were conducted to find latent factors, compared them with the composite approach, and to test for longitudinal (partial-)MI in a neuropsychiatric test battery, consisting of 14 test variables. A total of 330 elderly (mean age: 73.78 ± 1.52 years at baseline) were analyzed two times (3 years apart). RESULTS: EFA revealed a four-factor model representing declarative memory, attention, working memory, and visual-spatial processing. Based on CFA, an accurate model was estimated across both measurement timepoints. Partial non-MI was found for parameters such as loadings, test- and latent factor intercepts as well as latent factor variances. The latent factor approach was preferable to the composite approach. CONCLUSION: The overall assessment of non-MI latent factors may pose a possible target for this field of research. Hence, the non-MI of variances indicated variables that are especially suited for the prediction of pathological cognitive decline, while non-MI of intercepts indicated general aging-related decline. As a result, the sole assessment of MI may help distinguish pathological from normative aging processes and additionally may reveal compensatory neuropsychological mechanisms.

Evidence and expert consensus based German guidelines for the use of repetitive transcranial magnetic stimulation in depression.

INTRODUCTION: Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field. METHODS: The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations. FINDINGS: Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

Can smoking cessation be taught online? A prospective study comparing e-learning and role-playing in medical education.

OBJECTIVES: We compared the effect of different didactic formats - e - learning and role-playing - on medical students' knowledge and counselling skills in smoking cessation training. METHODS: At a German medical school, 145 third-year students were randomly allocated to attend an online course with video examples or an attendance course with role-playing. Students were trained in smoking cessation counselling according to the 5A's (ask, advise, assess, assist, arrange) for approximately 90 minutes. Practical skills were measured in an objective structured clinical examination (OSCE) and represent the primary endpoint of this prospective comparative study. Additionally, changes in theoretic knowledge were assessed by pre - and post - interventional questionnaires and a final written exam. RESULTS: In the OSCE, overall scores were higher in the attendance group (Mdn=70.8 % vs. 62.8 %; U=119; p=.087, n=36), but a statistical advantage was only found in one single counselling sequence ("Assist": Mdn=66.7 % vs. 51.4 %; p = .049) and the rating of the standardised patients (M=4.7 vs. 4.2 out of 5 points, t(27.836)=2.0, p=.028). Students' results (n=130) from self-assessment and written exams suggest that both approaches are equally well suited to increase theoretical knowledge. The online course was more time efficient (90 vs. 73 minutes). CONCLUSIONS: Seminar and web-based training seem equally well suited for transferring knowledge and skills on tobacco cessation counselling. Considering their particular strengths, these two teaching approaches could be combined.

Altered parietal brain oxygenation in Alzheimer's disease as assessed with near-infrared spectroscopy.

OBJECTIVE: Visuospatial deficits are among the first symptoms of Alzheimer disease (AD) and linked to lower activation in the superior parietal cortex as assessed with functional imaging. Near-infrared spectroscopy (NIRS) is an optical method to measure changes in the concentration of oxygenated hemoglobin and deoxygenated hemoglobin in the microvascular system of the cortex. Because of its advantages in measurement situation, NIRS has proven to be especially suited for investigating psychiatric patients. The aim of this study was to probe the activation of parietal regions in patients with AD, performing a visuospatial task by means of functional NIRS (fNIRS). METHODS: Thirteen patients with suspected mild AD and 13 healthy subjects comparable in age and gender were investigated while working on a modified version of the Benton Line Orientation Task. RESULTS: During the spatial task, healthy subjects showed explicit parietal activation, whereas patients displayed only activation during the control task. Interestingly, there was no difference in visuospatial performance between the two groups. CONCLUSION: The results indicate that fNIRS is able to measure parietal activation deficits in patients with AD, which could be developed into an early detection method in the future.

Neuronal correlates of the visual-spatial processing measured with functional near-infrared spectroscopy in healthy elderly individuals.

Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) are a globally rising issue. It is necessary to detect such diseases early to find strategies for prevention. Typically, patients with MCI or AD show deviant neuronal patterns, which could be detected early through brain imaging techniques enabling assumptions about pre-existing diseases. Functional Near-Infrared Spectroscopy (fNIRS) is an appropriate imaging method because of its easy and economical nature with hardly any drawbacks. An early measurable risk factor indicating neurodegenerative processes could be a deficit in visual-spatial processing, which is localized in the parietal cortex. In this study, we aimed to measure the hemodynamic response of the visual-spatial processing in the healthy elderly participants of our long-term Vogel Study with fNIRS during the clock-hand-angle-discrimination task (ADT) to deepen our understanding of healthy brain mechanisms. Our results revealed for our healthy sample a significantly increased neuronal brain activity with increasing task difficulties, namely from the long to the middle to the short clock hand during ADT and significantly higher activation in the right hemisphere compared to the left hemisphere as well as in the superior parietal cortex compared to the inferior parietal cortex. Additionally, our behavioral data demonstrated longer reaction times and more errors with an increasing task requirement. We, therefore, assume that visual-spatial processing can successfully be operationalized with fNIRS for healthy elderly people based on ADT. Further fNIRS analyses are planned to investigate pathological neuronal correlates of visual-spatial function in MCI or AD study participants.

Micronucleus frequency in buccal mucosa cells of patients with neurodegenerative diseases.

Neurodegenerative diseases show an increase in prevalence and incidence, with the most prominent example being Alzheimer's disease. DNA damage has been suggested to play a role in the pathogenesis, but the exact mechanisms remain elusive. We enrolled 425 participants with and without neurodegenerative diseases and analyzed DNA damage in the form of micronuclei in buccal mucosa samples. In addition, other parameters such as binucleated cells, karyolytic cells, and karyorrhectic cells were quantified. No relevant differences in DNA damage and cytotoxicity markers were observed in patients compared to healthy participants. Furthermore, other parameters such as lifestyle factors and diseases were also investigated. Overall, this study could not identify a direct link between changes in buccal cells and neurogenerative diseases, but highlights the influence of lifestyle factors and diseases on the human buccal cytome.

Neural response to reward anticipation is modulated by Gray's impulsivity.

According to the Reinforcement Sensitivity Theory (RST), Gray's dimension of impulsivity, reflecting human trait reward sensitivity, determines the extent to which stimuli activate the Behavioural Approach System (BAS). The potential neural underpinnings of the BAS, however, remain poorly understood. In the present study, we examined the association between Gray's impulsivity as defined by the RST and event-related fMRI BOLD-response to anticipation of reward in twenty healthy human subjects in brain regions previously associated with reward processing. Anticipation of reward during a Monetary Incentive Delay Task elicited activation in key components of the human reward circuitry such as the ventral striatum, the amygdala and the orbitofrontal cortex. Interindividual differences in Gray's impulsivity accounted for a significant amount of variance of the reward-related BOLD-response in the ventral striatum and the orbitofrontal cortex. Specifically, higher trait reward sensitivity was associated with increased activation in response to cues indicating potential reward. Extending previous evidence, here we show that variance in functional brain activation during anticipation of reward is attributed to interindividual differences regarding Gray's dimension of impulsivity. Thus, trait reward sensitivity contributes to the modulation of responsiveness in major components of the human reward system which thereby display a core property of the BAS. Generally, fostering our understanding of the neural underpinnings of the association of reward-related interindividual differences in affective traits might aid researchers in quest for custom-tailored treatments of psychiatric disorders, further disentangling the complex relationship between personality traits, emotion, and health.

Auricular vagus somatosensory evoked potentials in vascular dementia.

A new method for the assessment of vagus nerve function has recently been introduced into clinical practice. In the present study we could show that, contrary to our results in Alzheimer's disease (AD), in patients with vascular dementia (VaD) vagus sensory evoked potentials (VSEP) did not show statistically significant differences as compared to healthy controls. Thus, we hypothesize that the new method of VSEP could possibly contribute to a differential diagnosis between early cases of AD and VaD.