Alzheimer's disease camouflaged by histrionic personality disorder.

A common condition in Alzheimer's disease (AD) is unawareness of deficits. Different concepts try to elucidate the nature of this symptom. An essential question relates to the interaction of organic and psychogenic factors. Here we present a patient who displayed her cognitive deficits as attention-seeking behaviour. There was a history of histrionic personality disorder according to ICD-10 criteria. Unexpectedly, the final diagnosis after extensive diagnostic work-up was AD. The unusual coincidence of AD and a histrionic personality disorder hampered the clinical process of diagnosing dementia. We discuss unawareness as a complex concept incorporating neuroanatomical, psychiatric, and psychosocial aspects.

Tremor-correlated neuronal activity in the subthalamic nucleus of Parkinsonian patients.

Tremor in Parkinson's disease (PD) is generated by an oscillatory neuronal network consisting of cortex, basal ganglia and thalamus. The subthalamic nucleus (STN) which is part of the basal ganglia is of particular interest, since deep brain stimulation of the STN is an effective treatment for PD including Parkinsonian tremor. It is controversial if and how the STN contributes to tremor generation. In this study, we analyze neuronal STN activity in seven patients with Parkinsonian rest tremor who underwent stereotactic surgery for deep brain stimulation. Surface EMG was recorded from the wrist flexors and extensors. Simultaneously, neuronal spike activity was registered in different depths of the STN using an array of five microelectrodes. After spike-sorting, spectral coherence was analyzed between spike activity of STN neurons and tremor activity. Significant coherence at the tremor frequency was detected between EMG and neuronal STN activity in 76 out of 145 neurons (52.4%). In contrast, coherence in the beta band occurred only in 10 out of 145 neurons (6.9%). Tremor-coherent STN activity was widely distributed over the STN being more frequent in its dorsal parts (70.8-88.9%) than in its ventral parts (25.0-48.0%). Our results suggest that synchronous neuronal STN activity at the tremor frequency contributes to the pathogenesis of Parkinsonian tremor. The wide-spread spatial distribution of tremor-coherent spike activity argues for the recruitment of an extended network of subthalamic neurons for tremor generation.

Direct or indirect? Graphical models for neural oscillators.

Univariate and bivariate time series analysis techniques have enabled new insights into neural processes. However, these techniques are not feasible to distinguish direct and indirect interrelations in multivariate systems. To this aim multivariate times series techniques are presented and investigated by means of simulated as well as physiological time series. Pitfalls and limitations of these techniques are discussed.

Testing for directed influences among neural signals using partial directed coherence.

One major challenge in neuroscience is the identification of interrelations between signals reflecting neural activity. When applying multivariate time series analysis techniques to neural signals, detection of directed relationships, which can be described in terms of Granger-causality, is of particular interest. Partial directed coherence has been introduced for a frequency domain analysis of linear Granger-causality based on modeling the underlying dynamics by vector autoregressive processes. We discuss the statistical properties of estimates for partial directed coherence and propose a significance level for testing for nonzero partial directed coherence at a given frequency. The performance of this test is illustrated by means of linear and non-linear model systems and in an application to electroencephalography and electromyography data recorded from a patient suffering from essential tremor.

Thalamic gray matter changes in unilateral Parkinsonian resting tremor: a voxel-based morphometric analysis of 3-dimensional magnetic resonance imaging.

The thalamus is assumed to be involved in the generation of Parkinsonian tremor. Ten patients with tremor-dominant idiopathic Parkinson's disease (IPD) and strictly unilateral resting tremor were investigated by cerebral high-resolution 3-dimensional magnetic resonance imaging (MRI). MRI data were analyzed by an observer-independent morphometric technique, voxel-based morphometry (VBM). For VBM, MRI data were automatically normalized and segmented, then gray matter volumes were analyzed on a voxel-by-voxel basis in comparison to an age-matched control group using Statistical Parametric Mapping (SPM99). Highly significant structural changes, i.e. locally increased gray matter concentrations (P<0.001), were found in the nucleus ventralis intermedius (VIM) of the thalamus contralateral to the tremor side and were significantly covariant with tremor amplitudes. On the one hand, these changes were localized in close vicinity to a thalamic focal hypermetabolism as revealed by a previous positron emission tomography study in unilateral Parkinsonian tremor patients. On the other hand, the localization of the focal structural changes in VIM corresponds with the generally accepted target area of tremor surgery in IPD.

Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions. Report of two cases.

Holmes tremor is caused by structural lesions in the perirubral area of the midbrain. Patients often present with associated symptoms such as dystonia and paresis, which are usually refractory to medical therapy. Here, the authors describe two patients in whom both tremor and associated dystonia improved markedly following unilateral stimulation of the thalamic nucleus ventralis intermedius.

Neuronal correlates of clinical asymmetry in progressive supranuclear palsy.

PURPOSE: Progressive supranuclear palsy (PSP) is characterized by a symmetric hypokinetic syndrome with early falls and vertical supranuclear gaze palsy. However, clinically asymmetric manifestations occur, resembling idiopathic Parkinson disease or corticobasal degeneration. The aim of this study was to determine the neuronal correlates of patients suffering from PSP with a lateralized disease manifestation (hemi-PSP) in comparison to patients with symmetric clinical presentation (symPSP) and corticobasal degeneration. METHODS: Twenty-three patients with PSP and 8 patients with corticobasal degeneration according to standard diagnostic criteria underwent F-fluorodeoxyglucose (FDG) PET scans to assess disease-specific patterns of regional cerebral glucose metabolism reflecting neuronal activity. Group differences were analyzed by statistical parametric mapping and region-of-interest analyses. RESULTS: Clinically, 14 patients presented with symPSP while 9 patients were considered as hemi-PSP. Patients with symPSP or hemi-PSP showed similar bilateral medial frontal hypometabolism compared to corticobasal degeneration patients. In contrast, corticobasal degeneration patients exhibited a prominent parietal hypometabolism compared to both symPSP and hemi-PSP patients. SymPSP patients showed no significant hypometabolism compared to hemi-PSP, whereas hemi-PSP patients presented with significant hypometabolism of the motor thalamus, middle cingulate gyrus, and sensorimotor cortex contralateral to the most affected body side compared to symPSP patients. CONCLUSIONS: The present study demonstrates that a more pronounced and asymmetric involvement of cortical and subcortical motor areas is associated with a lateralized disease manifestation of PSP. Furthermore, these findings strongly suggest that FDG PET imaging may assist the challenging clinical differentiation between hemi-PSP and corticobasal degeneration by depicting disease-specific patterns of regional cerebral glucose metabolism.

123I-iodobenzamide SPECT is not an independent predictor of dopaminergic responsiveness in patients with suspected atypical parkinsonian syndromes.

UNLABELLED: The prediction of dopaminergic responsiveness in patients with parkinsonism is desirable for effective treatment strategies. We investigated whether striatal dopamine D2/D3 receptor (D2R) binding assessed by (123)I-iodobenzamide SPECT is an independent predictor of dopaminergic responsiveness in patients with parkinsonism. METHODS: Seventy-eight patients with clinically suspected atypical parkinsonian syndrome (APS) were prospectively recruited for imaging. To quantify striatal D2R binding, (123)I-iodobenzamide SPECT datasets were subjected to an observer-independent, regions-of-interest analysis. A final clinical diagnosis of Lewy-body disease (LBD) or APS was made after a mean follow-up of 12 mo. On the basis of follow-up data, dopaminergic responsiveness was classified as 0 (none), 1 (transient), 2 (sustained mild), or 3 (sustained strong). Uni- and multivariate analyses of the relationship between treatment response, D2R binding, and confounding variables were conducted. RESULTS: Sixty patients with clinically verified LBD (n = 28; 22/28 with Parkinson disease) or APS (n = 32), in whom dopaminergic responsiveness could be assessed (n = 19/13/15/13 in categories 0/1/2/3; 18 were excluded because of insufficient dosing), were included in the statistical analysis. Univariate analyses revealed that a sustained treatment response was significantly associated with higher D2R binding, clinical diagnosis of LBD, lower Hoehn and Yahr scores, and younger age. After multivariate correction of D2R binding for diagnosis, age, symptom duration, Hoehn and Yahr score, and dopaminergic pretreatment, no association was found between D2R binding and treatment response, either in the pooled group or in LBD or APS subgroups. CONCLUSION: Striatal D2R binding assessed by (123)I-iodobenzamide SPECT does not provide additional predictive information about treatment response beyond other clinical variables, most notably the clinical diagnosis.

Assessment of striatal dopamine D2/D3 receptor availability with PET and 18F-desmethoxyfallypride: comparison of imaging protocols suited for clinical routine.

UNLABELLED: Assessment of striatal dopamine receptor availability with (18)F-desmethoxyfallypride PET is of high diagnostic utility in parkinsonism. The present study was undertaken to define the optimal clinical scan protocol with regard to quantification accuracy and scan time. METHODS: Fourteen patients with parkinsonian syndromes underwent (18)F-desmethoxyfallypride PET over 90 min. Volume-of-interest analyses were performed after spatial normalization, with the right and left caudate nuclei and putamina as target regions and the cerebellum as reference region. The estimate of target region binding potential (relative to nondisplaceable radioligand in tissue) (BP(ND)) provided by the 2-step simplified reference tissue model (SRTM2) served as the reference standard. Additional analyses included the multilinear reference tissue model 2 (MRTM2), noninvasive graphical analyses, and single-scan analyses (peak-equilibrium analysis at 35-65 min [PEA]; pseudoequilibrium analysis at 60-90 min [PsEA]). RESULTS: SRTM2 and MRTM2 yielded virtually identical results (mean BP(ND) difference = 0.1% ± 0.5%, r(2) = 1.0). Noninvasive graphical analyses with and without inclusion of the k(2)' term were affected by a small BP(ND) bias (2.5% ± 3.6% and -5.0% ± 6.7%, respectively), although correlations with SRTM2 were still excellent (r(2) = 1.0 and 0.98, respectively). In turn, single-scan analyses suffered from limited precision (PEA, mean BP(ND) bias = 0.7% ± 13.0%, r(2) = 0.90) or a considerable positive bias (PsEA, 19.2% ± 7.1%, r(2) = 0.98). Shortening scan time to 70 and 60 min resulted in an acceptable average BP(ND) change (<5% decline) for SRTM2/MRTM2 and graphical analysis with inclusion of the k(2)' term, respectively. CONCLUSION: Kinetic reference tissue model analyses of (18)F-desmethoxyfallypride PET data offer the least biased results at a well-tolerable scan duration and should thus be pursued whenever possible. Single-scan analyses may be pragmatic alternatives that, however, suffer from a relevant positive bias (PsEA) or limited precision (PEA).

[¹8F]FDG-PET is superior to [¹²³I]IBZM-SPECT for the differential diagnosis of parkinsonism.

OBJECTIVE: Imaging of regional cerebral glucose metabolism with PET and striatal dopamine D2/D3 receptors (D2R) with SPECT improves the differential diagnosis of parkinsonism. We prospectively investigated 1) the diagnostic merits of these approaches in differentiating between Lewy body diseases (LBD; majority Parkinson disease [PD]) and atypical parkinsonian syndromes (APS); 2) the diagnostic value of [¹8F]fluorodeoxyglucose (FDG)-PET to differentiate among APS subgroups. METHODS: Ninety-five of 107 consecutive patients with clinically suspected APS referred for imaging were recruited. [¹8F]FDG-PET scans were analyzed by visual assessment (including individual voxel-based statistical maps). Based on a priori defined disease-specific patterns, patients with putative APS were differentiated from LBD (first level) and allocated to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD) (second level). [¹²³I] iodobenzamide (IBZM)-SPECT datasets were subjected to an observer-independent regions-of-interest analysis to assess striatal D2R availability. Movement disorder specialists made final clinical diagnoses after a median follow-up time of 12 months. RESULTS: Seventy-eight patients with clinically verified APS (n = 44) or LBD (n = 34) were included in the statistical analysis. The area under the receiver operating characteristic curve for discrimination between APS and LBD was significantly larger for [¹8F]FDG-PET (0.94) than for [¹²³I]IBZM-SPECT (0.74; p = 0.0006). Sensitivity/specificity of [¹8F]FDG-PET for diagnosing APS was 86%/91%, respectively. Sensitivity/specificity of [¹8F]FDG-PET in identifying APS subgroups was 77%/97% for MSA, 74%/95% for PSP, and 75%/92% for CBD. CONCLUSIONS: The diagnostic accuracy of [¹8F]FDG-PET for discriminating LBD from APS is considerably higher than for [¹²³I]IBZM-SPECT. [¹8F]FDG-PET reliably differentiates APS subgroups.

On the estimation of the direction of information flow in networks of dynamical systems.

The inference of the interaction structure in networks of dynamical systems promises novel insights into the functioning or malfunctioning of systems in the neurosciences. This may improve the understanding of mechanisms underlying several diseases like tremor disorders and might eventually help to cure patients. Of particular interest is the estimation of the direction of information flow for which different methods have been suggested and have been applied to data from human tremor. Based on a simulated system motivated by the human tremor application we analyze the performance of three methods. The abilities and limitations of the individual techniques are compared and discussed. An application to essential tremor complements this investigation.

High functional connectivity of tremor related subthalamic neurons in Parkinson's disease.

OBJECTIVE: Tremor is a core symptom of Parkinson's disease (PD). The subthalamic nucleus (STN) seems to be crucial for tremor pathophysiology considering that deep brain stimulation (DBS) of the STN leads to an effective reduction of Parkinsonian tremor. Here, we investigate the functional connectivity between STN neurons in patients with Parkinsonian tremor. METHODS: STN activity was analyzed in 7 patients with Parkinsonian rest tremor who underwent stereotactic surgery for DBS. Spike activity was registered in different depths of the STN using an array of five microelectrodes. Interneuronal coherence within the STN was analyzed. RESULTS: Significant interneuronal coherence at the tremor frequency was detected in 78 out of 145 neurons. In contrast, interneuronal coherence in the beta band occurred only in 26 out of 145 neurons. Functional connectivity at the tremor frequency can be characterized by a slowly decaying exponential curve which describes coherence between STN neurons as a function of interneuronal distances between 0 and 4mm. CONCLUSIONS: Spatially distributed synchronization at the tremor frequency seems to be a key feature of STN pathophysiology in patients with Parkinsonian tremor. SIGNIFICANCE: The findings suggest a subthalamic tremor network which is widely extended and strongly coupled.

Time-variant estimation of directed influences during Parkinsonian tremor.

The inference of interaction structures in multidimensional time series is a major challenge not only in neuroscience but in many fields of research. To gather information about the connectivity in a network from measured data, several parametric as well as non-parametric approaches have been proposed and widely examined. Today a lot of interest is focused on the evolution of the network connectivity in time which might contain information about ongoing tasks in the brain or possible dynamic dysfunctions. Therefore an extension of the current approaches towards time-resolved analysis techniques is desired. We present a parametric approach for time variant analysis, test its performance for simulated data, and apply it to real-world data.

Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy.

PURPOSE: The substantia nigra pars reticulata (SNpr) is assumed to be involved in the control of several kinds of epileptic seizures, an assumption based mostly on neuropharmacologic evidence. However, only very few neurophysiological recordings from the basal ganglia support neuropharmacologic data. We investigated the electrophysiologic activity of SNpr neurons in rats with genetic absence epilepsy. METHODS: Electrocorticography (ECoG) and multi-unit recordings using permanently implanted tetrodes were obtained in freely behaving rats. After spike sorting, auto- and cross-correlation analysis was used to detect oscillatory neuronal activities and synchronizations. RESULTS: During interictal periods, neither oscillation nor synchronization could be observed in the firing patterns of SNpr neurons. At the beginning of the absence seizure, the firing rate increased significantly. The SNpr neurons started firing in bursts of action potentials. Bursts were highly correlated to the spike-and-wave discharges (SWDs) in the ECoG, mainly after the spike component of the cortical spike-and-wave complex. Moreover, pairs of SNpr neurons tended to fire synchronously. Before the end of the seizure, the firing rate decreased progressively, and the burst-firing pattern ended at or before the end of the SWDs. Once the SWDs had stopped, the SNpr neurons resumed their basal firing pattern as before the seizure onset. CONCLUSIONS: These results provide electrophysiologic evidence that firing patterns and synchronization of SNpr neurons are in phase with the occurrence of SWDs. The findings support the concept that nigral control mechanisms are involved in modulating the propagation of an ongoing generalized seizure.