Reduced spontaneous low frequency oscillations as measured with functional near-infrared spectroscopy in mild cognitive impairment.

Spontaneous low frequency oscillations (LFO) in functional imaging data have gained increased interest in the study of cognitive decline. Persons diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD) display alterations in their amount of LFO in various brain regions. This is commonly interpreted as disruptions in the autoregulation of the cerebral microvascular system. In the present study LFO (0,07-0,11 Hz) were measured with 52-channel near-infrared spectroscopy (NIRS) in 61 healthy elderly persons (70-76 years), 54 MCI subjects (70-76 years) and 25 healthy young controls (21-48 years) during rest over the frontal and the parietal cortex. Both MCI and healthy elderly controls showed less LFO in the frontal cortex as compared to young subjects. For the parietal cortex a decrease in LFO could be observed for the MCI group in comparison to healthy elderly subjects. Correlations of more LFO with worse performance in neuropsychological tests point to compensatory processes. LFO measured with NIRS might be especially suited for longitudinal studies aiming at predicting cognitive decline.

Plasticity of Functional MAOA Gene Methylation in Acrophobia.

Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.

Decreased hemodynamic response in inferior frontotemporal regions in elderly with mild cognitive impairment.

The verbal fluency task (VFT) is a well-established cognitive marker for mild cognitive impairment (MCI) in the prodromal stage of Alzheimer´s dementia (AD). The behavioral VFT performance of patients allows the prediction of dementia two years later. But effective compensatory mechanism might cover or reduce the predictive value of the VFT. Therefore the aim of this study is to measure the hemodynamic response during VFT in patients with mild cognitive impairment (MCI) to establish the hemodynamic response during the VFT as a screening instrument for the prediction of dementia. One method which allows measuring the hemodynamic response during speech production without severe problems with moving artifacts like in functional magnetic resonance imaging (fMRI) is the functional near-infrared spectroscopy (fNIRS). It is optimal as a screening instrument, as it is easy to apply and without any contraindications. In this study we assessed the hemodynamic response in prefrontal and temporal regions in patients with MCI as well as matched healthy controls with fNIRS. We found a decreased hemodynamic response in the inferior frontotemporal cortex for the MCI group. Our results indicate that a frontotemporal decreased hemodynamic response could serve as a diagnostic biomarker for dementia.

Relevance of Dorsolateral and Frontotemporal Cortex on the Phonemic Verbal Fluency - A fNIRS-Study.

Non-invasive brain stimulation is widely used to investigate and manipulate specific brain functions to broaden knowledge about healthy people, and also to provide for a potential treatment option for people with various psychopathological disorders that do not adequately benefit from traditional treatments. Nevertheless, the underlying mechanisms have not been fully investigated yet. The aim of the present study was to investigate whether we could alter the brain activity during a test for executive functioning. Therefore, we measured the activity in the prefrontal cortex (PFC) using near-infrared spectroscopy (NIRS) while applying bilateral anodal and cathodal transcranial direct current stimulation (tDCS, 1 mA) to the left and right dorsolateral PFC (dlPFC) during the phonemic part of the verbal fluency test (VFT). A total of 61 young and healthy participants were divided into three groups: left anodal/right cathodal, left cathodal/right anodal stimulation or sham. All participants performed the letter-cued part of the VFT and a control task. Brain activation was simultaneously measured using NIRS. We found only the frontotemporal cortex (FTC) but not the dorsolateral prefrontal cortex (DLPFC) to be activated. Furthermore, stimulating the DLPFC bilaterally by tDCS showed no significant differences between the three different groups when performing the VFT, neither in performance nor in cortical activation. Instead, we found a significant increase in deoxygenated hemoglobin [HHb] while performing the control task in the left anodal/right cathodal stimulation group compared to sham. Interestingly, also an influence on the mood of our participants was observed. These results are of importance especially regarding a better understanding of the influence of the dlPFC on the VFT.

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.

Reduced Activity in the Right Inferior Frontal Gyrus in Elderly APOE-E4 Carriers during a Verbal Fluency Task.

Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer's disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70-77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT.

Medial prefrontal cortex stimulation accelerates therapy response of exposure therapy in acrophobia.

BACKGROUND: Animal as well as human research indicated that the ventral medial prefrontal cortex (vmPFC) is highly relevant for fear extinction learning. Recently, we showed that targeting the vmPFC with high-frequency repetitive transcranial magnetic stimulation (rTMS) in a placebo-controlled study with 45 healthy controls induced higher prefrontal activity during extinction of conditioned stimuli (CS+) in the active compared to the sham stimulated group and better extinction learning as indicated by ratings, fear potentiated startles and skin conductance responses. OBJECTIVE: In this study, we aimed to proof our concept of accelerating extinction learning using rTMS of the mPFC in a group of anxiety disorder patients. METHODS: To specifically evaluate the impact of rTMS on exposure-based therapy, we applied a sham-controlled protocol over the vmPFC (FPz) succeeded by a virtual reality exposure therapy (VRET) in n = 20 participants with acrophobia and n = 19 controls. RESULTS: We found a significantly higher reduction in active compared to sham stimulated group for anxiety (t[37] = 2.33, p < 0.05) as well as avoidance ratings t[37] = 2.34, p < 0.05) from pre to post therapy. CONCLUSION: This study provides first clinical evidence that high-frequency rTMS over the vmPFC improves exposure therapy response of acrophobia symptoms.