Jürgen Andrich

Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment.

A high sympathetic and/or a low cardiovagal activity in patients with major depression (MD) may contribute to the higher cardiac morbidity and mortality of MD patients. Standardized tests of heart rate variability (HRV) allow a quantitative estimation of autonomic nervous system function. However, previous studies on the relationship between HRV and MD have revealed conflicting results. Our study compared time and frequency domain HRV indices (5-min resting study, deep breathing test, Valsalva test) between 32 patients with MD (DSM-III-R) and 64 non-depressed controls. The severity of depressive symptoms was assessed by the Hamilton Depression Scale (HAM-D); patients were divided into subgroups with moderate (M-HAM-D<25) or severe depressive symptoms (S-HAM-D>or=25). After controlling for age, gender and smoking, S-HAM-D patients showed a higher heart rate and a significantly lower modulation of cardiovagal activity compared to controls. Although some of the HRV indices of the M-HAM-D group did not differ significantly from controls, they were in the expected direction. There was a significantly negative correlation between the HAM-D scores and the vagal HRV indices, suggesting a direct association between the severity of depressive symptoms and the modulation of cardiovagal activity. Clinical consequences arising from these findings and possible implications for treatment are discussed.

NR2A and NR2B receptor gene variations modify age at onset in Huntington disease

Abstract. N -Methyl- d -aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5′ part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N -methyl- d -aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.

PGC-1alpha as modifier of onset age in Huntington disease

Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In > 400 HD patients, a polymorphism located within intron 2, a potential recombination hot spot, explains a small, but statistically significant, amount of the variability in AO. Our data suggest that PGC-1alpha has modifying effects on the pathogenic process in HD.

Autonomic nervous system function in Huntington's disease

Objective: To investigate whether Huntingtons disease (HD) affects autonomic nervous system (ANS) functioning. Methods: Twenty patients with HD who had positive genetic test results underwent standardised ANS function tests including sympathetic skin responses (SSRs) of the hands and feet, measurements of heart rate variability (HRV), both during five minutes of resting and deep respiration, and an orthostatic blood pressure test. Patients were classified according to the motor subscale of the unified Huntingtons disease rating scale (UHDRS; mean (SD) score 26.4 (13.6)) and divided into two subgroups: UHDRS <25 points (early stages, E-HD) and UHDRS ≥25 points (mid stages, M-HD). Autonomic indices were compared with those obtained for a group of well matched healthy controls (n=60). Results: Overall, patients showed lower HRV indices than controls. Multivariate analysis with the independent factor of “group” (controls, E-HD, M-HD) showed a significant group effect on both the high frequency power (F=4.32, p=0.017) and the coefficient of variation (F=4.23, p=0.018), indicating a significant reduction in vagal modulation in the M-HD group. There was a shift in autonomic neurocardiac balance towards sympathetic predominance in the M-HD group compared with controls (F=2.89, p=0.062). Moreover, we found an inverse correlation between the severity of clinical HD symptoms (assessed by the UHDRS) and the modulation of cardiovagal activity (p=0.028). Vagal dysregulation was present in two patients; one of them also showed a pathological blood pressure test and a latency prolongation in the SSRs of the hands. Two other patients had pathologically reduced SSR amplitudes. Only patients of the M-HD group were affected. Conclusion: Autonomic dysfunction is present even in the middle stages of HD and affects both the sympathetic and parasympathetic branch of the ANS.

Response inhibition in Huntington's disease : A study using ERPs and sLORETA

Huntingtons disease (HD) is an autosomal dominant inherited neurodegenerative disorder, with neurodegeneration mainly affecting the striatum. We investigated executive functions related to response inhibition in (HD) and healthy controls by means of event-related potentials (ERP) in a simple Go/Nogo-task. In Nogo as opposed to Go trials two fronto-central ERP components are elicited: the Nogo-N2 and Nogo-P3. These components are supposed to depend on (medial) prefrontal regions, especially the anterior cingulate cortex (ACC). The results show that the Nogo-N2 did not differ between the groups, while the Nogo-P3 demonstrated a strong attenuation in the HD-group, which also showed more false alarms in the Nogo-condition. Using sLORETA it is shown that this attenuation was related to the medial frontal cortex, especially the ACC, and superior frontal cortex areas. Moreover, the attenuation was related to the underlying genetic disease load (CAG-index). The decline in inhibition is likely mediated via a dysfunction in the ACC, which is known to be dysfunctional in HD. Moreover, the results may be interpreted that the decline in response inhibition in HD is gene-associated. The differentially affected Nogo-components suggest that they rely on different neuronal circuits, even within the ACC. For HD this suggests that this structure is not entirely dysfunctional.

Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam, and lorazepam.

ObjectivesTo evaluate the effects of intravenously applied diazepam, lorazepam, and midazolam on autonomic neurocardiac regulation assessed by standardized measurements of heart rate variability. DesignProspective, randomized clinical study. SettingUniversity teaching hospital. PatientsForty-five patients, who underwent a gastroscopy, were randomly assigned to intravenous premedication with midazolam (5 mg), diazepam (10 mg), or lorazepam (4 mg). Six subjects refused an injection and served as nonpremedicated controls. InterventionsSerial recordings of the 5-min resting heart rate variability were obtained before and 15 and 30 mins after premedication. Seven benzodiazepine-treated patients received intravenous flumazenil (0.5 mg). Measurements and Main ResultsThe average doses applied were 0.07 mg/kg for midazolam, 0.13 mg/kg for diazepam, and 0.06 mg/kg for lorazepam. Fifteen minutes after intravenous benzodiazepines were administered, we found an increase in resting heart rate and a reduction of vagal tone compared with baseline in all three benzodiazepine-treated subgroups. Multivariate analysis (covariate age) of the changes in heart rate variability indices over the experimental course revealed a significant reduction in absolute high-frequency power with midazolam or diazepam compared with nonpremedicated subjects. Moreover, midazolam-treated subjects showed a significantly larger reduction in relative high-frequency power not only compared with nontreated subjects, but also compared with lorazepam- or diazepam-treated subjects. Vagal tone remained reduced compared with baseline even 30 mins after benzodiazepine application, however, the resting heart rate decreased toward baseline levels. After flumazenil administration, there was a linear correlation between an increase in high-frequency power and a corresponding decrease in resting heart rate. ConclusionsBenzodiazepines can influence autonomic neurocardiac regulation in man, probably through their interaction with the &ggr;-aminobutyric acidA-receptor chloride ion channel complex. The pattern of findings suggests that intravenous midazolam, diazepam, and lorazepam influence human autonomic neurocardiac regulation in a biphasic way. First, they cause a reduction of central vagal tone, and second, they may decrease the cardiac pacemaker directly. Flumazenil completely abolished the autonomic neurocardiac regulation effects of benzodiazepines.

Error Processing in Huntington's Disease

Background Huntingtons disease (HD) is a genetic disorder expressed by a degeneration of the basal ganglia inter alia accompanied with dopaminergic alterations. These dopaminergic alterations are related to genetic factors i.e., CAG-repeat expansion. The error (related) negativity (Ne/ERN), a cognitive event-related potential related to performance monitoring, is generated in the anterior cingulate cortex (ACC) and supposed to depend on the dopaminergic system. The Ne is reduced in Parkinsons Disease (PD). Due to a dopaminergic deficit in HD, a reduction of the Ne is also likely. Furthermore it is assumed that movement dysfunction emerges as a consequence of dysfunctional error-feedback processing. Since dopaminergic alterations are related to the CAG-repeat, a Ne reduction may furthermore also be related to the genetic disease load. Methodology/Principle Findings We assessed the error negativity (Ne) in a speeded reaction task under consideration of the underlying genetic abnormalities. HD patients showed a specific reduction in the Ne, which suggests impaired error processing in these patients. Furthermore, the Ne was closely related to CAG-repeat expansion. Conclusions/Significance The reduction of the Ne is likely to be an effect of the dopaminergic pathology. The result resembles findings in Parkinsons Disease. As such the Ne might be a measure for the integrity of striatal dopaminergic output function. The relation to the CAG-repeat expansion indicates that the Ne could serve as a gene-associated “cognitive” biomarker in HD.

fMRI reveals altered auditory processing in manifest and premanifest Huntington's disease

Structural alterations of the basal ganglia occur in patients with Huntingtons disease (HD). The aim of this exploratory study was to assess auditory processing mechanisms by functional MRI (fMRI) in patients with premanifest (pHD) and manifest HD to gain more insight in possible alterations in basal ganglia-thalamic circuits. Sixteen HD and 18 pHD as well as corresponding age- and gender-matched controls were included. The pHD group was divided into two subgroups close (cpHD; <10 years) and far pHD (fcHP; >10 years), according to their estimated age of disease onset (eAO). Tone perception and processing were visualized by 3T fMRI by employing repeated tone stimulation through digitally generated pulsed (nu=5Hz) 800-Hz sine tones. We found altered activation in basal ganglia-thalamic circuits in HD and/or pHD compared to controls. (i) The cpHD group presented predominantly down-regulated processes compared to fpHD and HD. (ii) HD presented stronger bilateral activation of the putamen and (iii) fpHD presented stronger bilateral activation of the thalamus and also right caudatum. (iv) Depending on the progress of the disease, a shift towards the activation of more right hemispherical areas can be observed. Our findings seem to reflect an altered activation pattern to auditory stimulation depending on the progression of neuronal dysfunction in HD and pHD. They also stress the involvement of the basal ganglia-thalamic circuits in the processing of sensory auditory stimuli.

Functional compensation or pathology in cortico-subcortical interactions in preclinical Huntington's disease?

Huntingtons disease (HD) is an autosomal dominant neurological disorder, with degeneration amongst others affecting the basal ganglia dopaminergic system. Recent findings suggest compensatory as well as pathogenetic mechanisms mediated via the adenosine receptor system in the presymptomatic stage (pHD) of HD. The adenosine receptor system is functionally related to the dopaminergic system. In this study, we assessed error processing, a dopamine-dependent cognitive function, using an event-related potential the error negativity (Ne/ERN) in pHD and controls. This was done by means of a flanker task. The Ne consists of a cognitive and a motor component, expressed via different frequency bands. Time-frequency decomposition of the Ne into delta and theta sub-components was applied to assess if degeneration or compensation predominantly involve cognitive or motor processes. No parameter of the behavioral data (reaction times, error frequency, corrections, post-error slowing) differed between the groups. A selective increase in the power of the cognitive delta-Ne component was found in pHD relative to controls inversely related to the estimated age of onset (eAO). Thus, the increase in the power of the cognitive delta-Ne component was stronger in pHD with an earlier eAO. An earlier eAO implies stronger pathogenetic mechanisms. Due to the behavioral data our results speak for a solely cognitive compensating-mechanism controlling performance monitoring in pHD. In contrast, correlations with eAO suggest that the increase in delta-Ne activity is also related to pathogenesis. It is proposed that compensation is a transient effect of the whole pathogenetic dynamics of HD, with these two processes not foreclosing each other.

Levels of error processing in Huntington's disease: A combined study using event-related potentials and voxel-based morphometry

Huntingtons Disease (HD) is a neurogenetic disorder accompanied by an atrophy of the striatum and hence of the dopaminergic (DA) system. Neural processes subserving error processing presumably depend on the DA system. We assessed error processing in manifest HD and in presymptomatic HD‐gene‐mutation‐carriers (pHD) with event‐related potentials reflecting error processing (the error negativity or error‐related negativity and the error positivity derived from a flanker‐task. We found a reduction of the Ne in the case of HD compared to pHD reflecting dopamine system pathology. Despite the Ne being reduced in HD, behavioral adaptation was possible. In addition, the error‐rates did not differ between the groups. Optimized voxel‐based morphometry revealed that grey matter volume in the medial frontal gyrus is correlated with the Ne amplitude in symptomatic patients. In addition, the effect of a Ne‐reduction was related to the grey matter underneath the medial frontal gyrus, which is in line with two theories of the Ne. In contrast, the Pe did not differ between the groups, suggesting that the Pe is decoupled from the DA system. Interestingly we found a reduction of a late slow negativity on correct responses, which possibly reflects decreased preparatory processes in HD compared to pHD as induced by the DA alterations in HD. In conclusion a deterioration in error processing in HD compared to pHD is mainly reflected by the Ne. The deterioration might rely on two factors: a neurofunctional and a neuroanatomical. Hum Brain Mapp 2008.