Prognostic biomarkers in primary progressive multiple sclerosis: Validating and scrutinizing multimodal evoked potentials.

OBJECTIVE: To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities. METHODS: Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0-6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression. RESULTS: Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45-0.69; p < 0.01) and follow-up (Rho: 0.59-0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R2adj: 0.24), while EDSS and age did not. Tibial qSEP (R2adj: 0.22) and qMEP (R2adj: 0.26) were the best single modality predictors, outperformed by their combination (R2adj: 0.32). CONCLUSIONS: Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. SIGNIFICANCE: Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS.

From swing to cane: Sex differences of EEG resting-state temporal patterns during maturation and aging.

While many insights on brain development and aging have been gained by studying resting-state networks with fMRI, relating these changes to cognitive functions is limited by the temporal resolution of fMRI. In order to better grasp short-lasting and dynamically changing mental activities, an increasing number of studies utilize EEG to define resting-state networks, thereby often using the concept of EEG microstates. These are brief (around 100 ms) periods of stable scalp potential fields that are influenced by cognitive states and are sensitive to neuropsychiatric diseases. Despite the rising popularity of the EEG microstate approach, information about age changes is sparse and nothing is known about sex differences. Here we investigated age and sex related changes of the temporal dynamics of EEG microstates in 179 healthy individuals (6-87 years old, 90 females, 204-channel EEG). We show strong sex-specific changes in microstate dynamics during adolescence as well as at older age. In addition, males and females differ in the duration and occurrence of specific microstates. These results are of relevance for the comparison of studies in populations of different age and sex and for the understanding of the changes in neuropsychiatric diseases.

[Cognitive Behavioral Therapy for Anxiety and Depression in Patients with Parkinson's Disease]. / Kognitive Verhaltenstherapie von Angst und Depression bei Patienten mit Morbus Parkinson.

Non-motor symptoms in patients with Parkinson's disease (PD) are gaining more and more interest. Diagnosis of mental disorders in particular, such as anxiety and depression, are often not a part of the professional's diagnostic procedure in spite of the high prevalence rate. To provide these patients with comprehensive treatment, proper diagnosis and appropriate therapy are required. Cognitive Behavioral Therapy (CBT) has been one of the most efficient therapies for anxiety and depression, also in a group setting. This review compares studies that examined patients with PD diagnosed with anxiety disorders and/or depression. In eight studies, CBT in an individual setting was assessed. Three of these had a single case study design, three did not have a control group and two were randomized controlled trials. Two interventions were telephone-based and two were in a group therapy setting. Several results indicate that there is a decline in depressive symptoms as well as anxiety after CBT. There are very few randomized controlled studies on this issue. The efficacy of group treatment needs to be investigated better in order to offer patients effective treatment, keeping in kind their special circumstances.

[German Translation and Validation of the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's disease (SEND-PD)]. / Deutsche Übersetzung und Validierung der Checkliste zur Erfassung neuropsychiatrischer Störungen bei Parkinsonerkrankung (CENS-PE).

OBJECTIVE: The aim of the present study was to validate and provide a German version of the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's disease (SEND-PD) of Martínez-Martín et al. (2012). METHOD: The German version of the SEND-PD was evaluated in a sample consisting of 96 patients with Parkinson's disease (PD) (mean age: 65.3 years ±â€Š9.6, 29 female). This scale includes 12 items, representing the domains psychotic symptoms, mood/apathy and impulse control disorders. Reliability and validity analyses were conducted. RESULTS: The examined patients presented a few neuropsychiatric symptoms. Explorative factor analyses identified the proposed three dimensions solution. The items of the mood/apathy domain were homogenous and selective, and the domain showed acceptable internal consistency. For the other two domains, the values were only partially acceptable. Convergent, discriminate and construct validity were shown. CONCLUSION: The German version of the SEND-PD is sufficiently reliable and valid to be adopted in German speaking countries. However, since patients showed only a few symptoms in the dimensions of psychotic symptoms and impulse control disorders, these two domains can be evaluated only to a limited extent.

Reliability of fully automated versus visually controlled pre- and post-processing of resting-state EEG.

OBJECTIVE: To compare the reliability of a newly developed Matlab® toolbox for the fully automated, pre- and post-processing of resting state EEG (automated analysis, AA) with the reliability of analysis involving visually controlled pre- and post-processing (VA). METHODS: 34 healthy volunteers (age: median 38.2 (20-49), 82% female) had three consecutive 256-channel resting-state EEG at one year intervals. Results of frequency analysis of AA and VA were compared with Pearson correlation coefficients, and reliability over time was assessed with intraclass correlation coefficients (ICC). RESULTS: Mean correlation coefficient between AA and VA was 0.94±0.07, mean ICC for AA 0.83±0.05 and for VA 0.84±0.07. CONCLUSION: AA and VA yield very similar results for spectral EEG analysis and are equally reliable. AA is less time-consuming, completely standardized, and independent of raters and their training. SIGNIFICANCE: Automated processing of EEG facilitates workflow in quantitative EEG analysis.

Prediction of MS disability by multimodal evoked potentials: investigation during relapse or in the relapse-free interval?

OBJECTIVE: Little is known about optimal timing of multimodal evoked potential (EP)-investigations regarding prediction of MS disability. The aim of this study was to investigate whether timing of EP-investigations during a relapse or in the relapse-free interval influences prediction of MS disability. METHODS: Two groups of MS patients with similar age and gender distributions received visual, motor and somatosensory EPs either during a relapse (Group 1) or in the relapse-free interval (Group 2). Expanded Disability Status Score (EDSS) was obtained at baseline (T0) and year 3 (T2). Linear regression analysis was performed to examine the association between EDSS(T2) and a baseline EP compound measure (s-EP-Q(T0)) for each group. RESULTS: Median EDSS(T0) was 3.0 for Group 1 and 1.5 for Group 2. Mean disease durations were 2.0 and 2.8 years, respectively. Median EDSS(T2) was 2.0 for both groups. The s-EP-Q(T0) significantly predicted EDSS(T2) (R(2)=0.47) for patients in Group 2, but not for patients in Group 1 (R(2)=0.07). CONCLUSION: In early MS the functional remnants of relapses are a better predictor for development of medium-term disability than is the extent of impulse propagation impairment measured during relapse. SIGNIFICANCE: This suggests a role of multimodal EPs in prediction of MS disability if performed in the relapse-free interval.

Quantitative EEG and apolipoprotein E-genotype improve classification of patients with suspected Alzheimer's disease.

OBJECTIVE: To establish a model for better identification of patients in very early stages of Alzheimer's disease, AD (including patients with amnestic MCI) using high-resolution EEG and genetic data. METHODS: A total of 26 patients in early stages of probable AD and 12 patients with amnestic MCI were included. Both groups were similar in age and education. All patients had a comprehensive neuropsychological examination and a high resolution EEG. Relative band power characteristics were calculated in source space (LORETA inverse solution for spectral data) and compared between groups. A logistic regression model was calculated including relative band-power at the most significant location, ApoE status, age, education and gender. RESULTS: Differences in the delta band at 34 temporo-posterior source locations (p<.01) between AD and MCI groups were detected after correction for multiple comparisons. Classification slightly increased when ApoE status was added (p=.06 maximum likelihood test). Adjustment of analyses for the confounding factors age, gender and education did not alter results. CONCLUSIONS: Quantitative EEG (qEEG) separates between patients with amnestic MCI and patients in early stages of probable AD. Adding information about Apo ε4 allele frequency slightly enhances diagnostic accuracy. SIGNIFICANCE: qEEG may help identifying patients who are candidates for possible benefit from future disease modifying treatments.

[Prediction of psychosis by stepwise multilevel assessment--the Basel FePsy (Early Recognition of Psychosis)-Project]. / Vorhersage von Psychosen durch stufenweise Mehrebenenabklärung--Das Basler FePsy(Früherkennung von Psychosen)-Projekt.

BACKGROUND: We have conducted various studies in Basel with the aim of improving the methods for the early detection of psychosis (Früherkennung von Psychosen, FePsy). METHODS: From 1.3.2000 to 29.2.2004 234 individuals were screened using the Basel Screening Instrument for Psychosis (BSIP). 106 patients were identified as at risk for psychosis; out of these 53 remained in follow-up for up to 7 years (mean 5.4 years). The assessments were done with a specifically developed instrument for history taking, various scales for the psychopathology, assessments of neuropsychology and fine motor functioning, clinical and quantitative EEG, MRI of the brain, laboratory etc. RESULTS: Based on the BSIP alone, a relatively reliable prediction was possible: 21 (39.6%) of the individuals identified as at risk developed psychosis within the follow-up time. Post-hoc prediction could be improved to 81% by weighting psychopathology and including neuropsychology. Including the other domains obviously allows further improvements of prediction. CONCLUSIONS: The risk for psychosis should be assessed in a stepwise procedure. In a first step, a clinically oriented screening should be conducted. If an at-risk status is found, further assessments in various domains should be done in a specialised centre.

Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers.

The pharmacokinetics and pharmacodynamics of a highly concentrated cyclodextrin-based intranasal (i.n.) midazolam formulation containing the absorption-enhancer chitosan were studied in 12 healthy volunteers and compared with intravenous (i.v.) midazolam. The pharmacodynamic (PD) effects were assessed using quantitative electroencephalography (EEG). Maximal plasma concentrations of 63 and 110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n. midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam, the times to onset of significant EEG effects in the ß2 band (18-25 Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively. A sigmoid maximum-effect (E(max)) model indicated disequilibrium between plasma and effect-site concentrations, with equilibration half-lives of 2.1-4.8 min. The observed pharmacokinetic-PD (PK-PD) properties suggest that i.n. midazolam deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose, e.g., in out-of-hospital emergency settings with no immediate i.v. access.

Prediction of long-term disability in multiple sclerosis.

BACKGROUND: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS). OBJECTIVE: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years. METHODS: A total of 30 patients with relapsing-remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images). EDSS was again assessed at year 14 (T4). The association between evoked potential (EP), magnetic resonance (MR) data and EDSS was measured using Spearman's rank correlation. Multivariable linear regression was performed to predict EDSS(T4) as a function of z-transformed EP-latencies(T0). The model was validated using a jack-knife procedure and the potential for improving it by inclusion of additional baseline variables was examined. RESULTS: EDSS values(T4) correlated with the sum of z-transformed EP-latencies(T0) (rho = 0.68, p < 0.0001), but not with MR-parameters(T0). EDSS(T4) as predicted by the formula EDSS(T4) = 4.194 + 0.088 * z-score P100(T0) + 0.071 * z-score CMCT(UE, T0) correlated with the observed values (rho = 0.69, p < 0.0001). CONCLUSION: Combined EPs allow prediction of long-term disability in small groups of patients with MS. This may have implications for the choice of monitoring methods in clinical trials and for daily practice decisions.

Cutaneous silent periods are not affected by the antihistaminic drug cetirizine.

OBJECTIVE: Noxious digital nerve stimulation leads to transient suppression of the electromyographic activity in isometrically contracted hand muscles, known as the "cutaneous silent period" (CSP). To date, neurotransmitters potentially involved in mediating this electromyographic (EMG) suppression remain unknown. Anecdotal observation lead to the hypothesis that antihistaminic medication may counteract nociceptive EMG suppression, as CSPs in one male subject who was accustomed to CSP recordings were temporarily lost following ingestion of an antihistaminic drug for acute rhinitis. A second otherwise healthy male subject, who was on long-term cetirizine for allergic rhinitis, presented without clearly defined CSPs when volunteering for normal values. METHODS: We undertook a systematic study in five healthy subjects (including the one with temporarily lost CSPs) who underwent serial CSP testing after ingestion of 10 mg cetirizine. CSPs were elicited in thenar muscles following digit II and digit V stimulation (20 times sensory threshold, 100 sweeps rectified and averaged) before and 90, 180, and 360 min following intake of medication. RESULTS: CSP onset latency, CSP end latency and CSP duration, as well as the index of suppression did not change significantly following ingestion of 10 mg cetirizine. Repeat study in the subject with no clearly defined CSPs on long-term treatment revealed persistently absent CSPs after a 5-week withdrawal from cetirizine. CONCLUSION: CSPs are not affected by therapeutic doses of the H1 antihistaminic cetirizine. SIGNIFICANCE: Our findings suggest that histamine plays no major role as a neurotransmitter of CSPs.

Olfactory-induced brain activity in Parkinson's disease relates to the expression of event-related potentials: a functional magnetic resonance imaging study.

Olfactory disorders are common in patients with idiopathic Parkinson's disease (IPD). In IPD patients with hyposmia olfactory event-related potentials (ERPs) are typically found to be delayed or absent. Altered ERPs in IPD patients may also be consistent with reduced neuronal activity in the medial temporal lobe following olfactory stimulation, as demonstrated by functional magnetic resonance imaging (fMRI). We analyzed ERPs and fMRI scans of hyposmic IPD patients (n=18) to gain further insight about the brain regions involved in generation of olfactory ERPs. Patients were separated into two groups (n=9 per group), based on the detectability (+) or non-detectability (-) of ERPs. Central activation during olfactory stimulation was examined using fMRI. Both ERP+ and ERP- patients showed activity in brain areas relevant to olfactory processing, such as the amygdala, parahippocampal regions, and temporal regions (BA 37, 21/22). Comparison of both groups revealed higher activation in ERP+ patients, especially in the amygdala, parahippocampal cortex, inferior frontal gyrus (BA 47), insula, cingulate gyrus, striatum, and inferior temporal gyrus. The relationship between the expression of olfactory ERPs and cortical activation patterns seen during olfactory stimulation in fMRI in IPD patients supports the idea that ERPs are a sensitive marker of neurodegeneration in olfactory regions. In accordance with current neuropathological staging concepts, olfactory ERPs may be reflecting pathological changes in olfactory regions, independent of the typically observed nigro-striatal degeneration in IPD. Reduced activation of primary olfactory areas in the ERP-group may reflect a severe disruption of olfactory processing in these patients.

Functional imaging of the cerebral olfactory system in patients with Parkinson's disease.

BACKGROUND: Olfactory dysfunction is a frequent non-motor symptom in Parkinson's disease (PD) and is considered to be an early manifestation of the disease. OBJECTIVE: To establish the cortical basis of olfactory function in patients with PD. METHOD: Functional magnetic resonance imaging (fMRI) was used to investigate brain activity related to olfactory processing in patients with hyposmic PD at mild to moderate stages of the disease (n = 12, median Hoehn and Yahr stage 2.0) and in healthy, age-matched controls (n = 16) while passively perceiving a positively valenced (rose-like) odorant. RESULTS: In both patients with PD and healthy controls, olfactory stimulation activated brain regions relevant for olfactory processing (ie the amygdaloid complex, lateral orbitofrontal cortex, striatum, thalamus, midbrain and the hippocampal formation). In controls, a bilateral activation of the amygdala and hippocampus was observed, whereas patients with PD involved these structures in the left hemisphere only. Group comparison showed that regions of higher activation in patients with PD were located bilaterally in the inferior frontal gyrus (BA 44/45) and anterior cingulate gyrus (BA 24/32), and the left dorsal and right ventral striatum. CONCLUSIONS: In patients with PD, results obtained under the specific conditions used suggest that neuronal activity in the amygdala and hippocampus is reduced. Assuming an impact on olfactory-related regions early in PD, our findings support the idea that selective impairment of these brain regions contributes to olfactory dysfunction. Furthermore, neuronal activity in components of the dopaminergic, cortico-striatal loops appears to be upregulated, indicating that compensatory processes are involved. This mechanism has not yet been demonstrated during olfactory processing in PD.

The Basel early-detection-of-psychosis (FEPSY)-study--design and preliminary results.

UNLABELLED: Early detection and therapy of schizophrenic psychoses have become broadly accepted aims in psychiatry, recently even in very early stages of the disorder when clear diagnostic criteria are not yet fulfilled. However, reliable and widely applicable methods do not yet exist. This study aims at contributing to the improvement of the early assessment of psychosis. METHOD: Individuals potentially at risk are identified by a newly developed stepwise screening procedure. Identified subjects are then examined extensively and followed-up for at least 5 years to detect actual transition to psychosis. RESULTS: Of 50 subjects who have been followed up for 1-5 years by now, 16 have progressed to frank psychosis, 12 of them during the first 12 months of follow-up. CONCLUSION: At this stage, our approach seems to be promising for the early detection of psychosis. Further results from this ongoing study will hopefully permit us to optimize the assessment procedure.

Obsessive-compulsive disorder due to neuroacanthocytosis treated with citalopram. A case report.

Neuroacanthocytois is a rare hereditary disease, which causes a degeneration of the striatum. Patients develop a choreatic movement disorder and also complex psychiatric symptoms, such as psychosis or Tourette's syndrome. We report a case of obsessive-compulsive disorder due to neuroacanthocytosis. The striatum plays an important role in the pathophysiology of obsessive-compulsive disorder. In Huntington's disease we also find obsessive-compulsive disorders, due to impairment of the fronto-striatal loop. Encouraged by similar pathophysiology and promising reports of selective serotonin reuptake inhibitors in this disease, we started a treatment with citalopram to which the patient responded very well.