Self-reported symptoms and motor tests via telemetry in a 36-month levodopa-carbidopa intestinal gel infusion trial

Objective To investigate if a home environment test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression. Background Seventy-seven patients diagnosed with advanced PD were recruited in an open longitudinal 36-month study at 10 clinics in Sweden and Norway; 40 of them were treated with levodopa-carbidopa intestinal gel (LCIG) and 37 patients were candidates for switching from oral PD treatment to LCIG. They utilized a mobile device test battery, consisting of self-assessments of symptoms and objective measures of motor function through a set of fine motor tests (tapping and spiral drawings), in their homes. Both the LCIG-naïve and LCIG-non-naïve patients used the test battery four times per day during week-long test periods. Methods Assessments The LCIG-naïve patients used the test battery at baseline (before LCIG), month 0 (first visit; at least 3 months after intraduodenal LCIG), and thereafter quarterly for the first year and biannually for the second and third years. The LCIG-non-naïve patients used the test battery from the first visit, i.e. month 0. Out of the 77 patients, only 65 utilized the test battery; 35 were LCIG-non-naïve and 30 LCIG-naïve. In 20 of the LCIG-naïve patients, assessments with the test battery were available during oral treatment and at least one test period after having started infusion treatment. Three LCIG-naïve patients did not use the test battery at baseline but had at least one test period of assessments thereafter. Hence, n=23 in the LCIG-naïve group. In total, symptom assessments in the full sample (including both patient groups) were collected during 379 test periods and 10079 test occasions. For 369 of these test periods, clinical assessments including UPDRS and PDQ-39 were performed in afternoons at the start of the test periods. The repeated measurements of the test battery were processed and summarized into scores representing patients’ symptom severities over a test period, using statistical methods. Six conceptual dimensions were defined; four subjectively-reported: ‘walking’, ‘satisfied’, ‘dyskinesia’, and ‘off’ and two objectively-measured: ‘tapping’ and ‘spiral’. In addition, an ‘overall test score’ (OTS) was defined to represent the global health condition of the patient during a test period. Statistical methods Change in the test battery scores over time, that is at baseline and follow-up test periods, was assessed with linear mixed-effects models with patient ID as a random effect and test period as a fixed effect of interest. The within-patient variability of OTS was assessed using intra-class correlation coefficient (ICC), for the two patient groups. Correlations between clinical rating scores and test battery scores were assessed using Spearman’s rank correlations (rho). Results In LCIG-naïve patients, mean OTS compared to baseline was significantly improved from the first test period on LCIG treatment until month 24. However, there were no significant changes in mean OTS scores of LCIG-non-naïve patients, except for worse mean OTS at month 36 (p<0.01, n=16). The mean scores of all subjectively-reported dimensions improved significantly throughout the course of the study, except ‘walking’ at month 36 (p=0.41, n=4). However, there were no significant differences in mean scores of objectively-measured dimensions between baseline and other test periods, except improved ‘tapping’ at month 6 and month 36, and ‘spiral’ at month 3 (p<0.05). The LCIG-naïve patients had a higher within-subject variability in their OTS scores (ICC=0.67) compared to LCIG-non-naïve patients (ICC=0.71). The OTS correlated adequately with total UPDRS (rho=0.59) and total PDQ-39 (rho=0.59). Conclusions In this 3-year follow-up study of advanced PD patients treated with LCIG we found that it is possible to monitor PD progression over time using a home environment test battery. The significant improvements in the mean OTS scores indicate that the test battery is able to measure functional improvement with LCIG sustained over at least 24 months.

Automatic spiral analysis for objective assessment of motor symptoms in Parkinson's disease

Objective: To develop a method for objective quantification of PD motor symptoms related to Off episodes and peak dose dyskinesias, using spiral data gathered by using a touch screen telemetry device. The aim was to objectively characterize predominant motor phenotypes (bradykinesia and dyskinesia), to help in automating the process of visual interpretation of movement anomalies in spirals as rated by movement disorder specialists. Background: A retrospective analysis was conducted on recordings from 65 patients with advanced idiopathic PD from nine different clinics in Sweden, recruited from January 2006 until August 2010. In addition to the patient group, 10 healthy elderly subjects were recruited. Upper limb movement data were collected using a touch screen telemetry device from home environments of the subjects. Measurements with the device were performed four times per day during week-long test periods. On each test occasion, the subjects were asked to trace pre-drawn Archimedean spirals, using the dominant hand. The pre-drawn spiral was shown on the screen of the device. The spiral test was repeated three times per test occasion and they were instructed to complete it within 10 seconds. The device had a sampling rate of 10Hz and measured both position and time-stamps (in milliseconds) of the pen tip. Methods: Four independent raters (FB, DH, AJ and DN) used a web interface that animated the spiral drawings and allowed them to observe different kinematic features during the drawing process and to rate task performance. Initially, a number of kinematic features were assessed including ‘impairment’, ‘speed’, ‘irregularity’ and ‘hesitation’ followed by marking the predominant motor phenotype on a 3-category scale: tremor, bradykinesia and/or choreatic dyskinesia. There were only 2 test occasions for which all the four raters either classified them as tremor or could not identify the motor phenotype. Therefore, the two main motor phenotype categories were bradykinesia and dyskinesia. ‘Impairment’ was rated on a scale from 0 (no impairment) to 10 (extremely severe) whereas ‘speed’, ‘irregularity’ and ‘hesitation’ were rated on a scale from 0 (normal) to 4 (extremely severe). The proposed data-driven method consisted of the following steps. Initially, 28 spatiotemporal features were extracted from the time series signals before being presented to a Multilayer Perceptron (MLP) classifier. The features were based on different kinematic quantities of spirals including radius, angle, speed and velocity with the aim of measuring the severity of involuntary symptoms and discriminate between PD-specific (bradykinesia) and/or treatment-induced symptoms (dyskinesia). A Principal Component Analysis was applied on the features to reduce their dimensions where 4 relevant principal components (PCs) were retained and used as inputs to the MLP classifier. Finally, the MLP classifier mapped these components to the corresponding visually assessed motor phenotype scores for automating the process of scoring the bradykinesia and dyskinesia in PD patients whilst they draw spirals using the touch screen device. For motor phenotype (bradykinesia vs. dyskinesia) classification, the stratified 10-fold cross validation technique was employed. Results: There were good agreements between the four raters when rating the individual kinematic features with intra-class correlation coefficient (ICC) of 0.88 for ‘impairment’, 0.74 for ‘speed’, 0.70 for ‘irregularity’, and moderate agreements when rating ‘hesitation’ with an ICC of 0.49. When assessing the two main motor phenotype categories (bradykinesia or dyskinesia) in animated spirals the agreements between the four raters ranged from fair to moderate. There were good correlations between mean ratings of the four raters on individual kinematic features and computed scores. The MLP classifier classified the motor phenotype that is bradykinesia or dyskinesia with an accuracy of 85% in relation to visual classifications of the four movement disorder specialists. The test-retest reliability of the four PCs across the three spiral test trials was good with Cronbach’s Alpha coefficients of 0.80, 0.82, 0.54 and 0.49, respectively. These results indicate that the computed scores are stable and consistent over time. Significant differences were found between the two groups (patients and healthy elderly subjects) in all the PCs, except for the PC3. Conclusions: The proposed method automatically assessed the severity of unwanted symptoms and could reasonably well discriminate between PD-specific and/or treatment-induced motor symptoms, in relation to visual assessments of movement disorder specialists. The objective assessments could provide a time-effect summary score that could be useful for improving decision-making during symptom evaluation of individualized treatment when the goal is to maximize functional On time for patients while minimizing their Off episodes and troublesome dyskinesias.

Automatic spiral analysis for objective assessment of motor symptoms in Parkinson's disease

A challenge for the clinical management of advanced Parkinson’s disease (PD) patients is the emergence of fluctuations in motor performance, which represents a significant source of disability during activities of daily living of the patients. There is a lack of objective measurement of treatment effects for in-clinic and at-home use that can provide an overview of the treatment response. The objective of this paper was to develop a method for objective quantification of advanced PD motor symptoms related to off episodes and peak dose dyskinesia, using spiral data gathered by a touch screen telemetry device. More specifically, the aim was to objectively characterize motor symptoms (bradykinesia and dyskinesia), to help in automating the process of visual interpretation of movement anomalies in spirals as rated by movement disorder specialists. Digitized upper limb movement data of 65 advanced PD patients and 10 healthy (HE) subjects were recorded as they performed spiral drawing tasks on a touch screen device in their home environment settings. Several spatiotemporal features were extracted from the time series and used as inputs to machine learning methods. The methods were validated against ratings on animated spirals scored by four movement disorder specialists who visually assessed a set of kinematic features and the motor symptom. The ability of the method to discriminate between PD patients and HE subjects and the test-retest reliability of the computed scores were also evaluated. Computed scores correlated well with mean visual ratings of individual kinematic features. The best performing classifier (Multilayer Perceptron) classified the motor symptom (bradykinesia or dyskinesia) with an accuracy of 84% and area under the receiver operating characteristics curve of 0.86 in relation to visual classifications of the raters. In addition, the method provided high discriminating power when distinguishing between PD patients and HE subjects as well as had good test-retest reliability. This study demonstrated the potential of using digital spiral analysis for objective quantification of PD-specific and/or treatment-induced motor symptoms.

The forward- and the equity-premium puzzles: two symptoms of the same illness?

In this paper we revisit the relationship between the equity and the forward premium puzzles. We construct return-based stochastic discount factors under very mild assumptions and check whether they price correctly the equity and the foreign currency risk premia. We avoid log-linearizations by using moments restrictions associated with euler equations to test the capacity of our return-based stochastic discount factors to price returns on the relevant assets. Our main finding is that a pricing kernel constructed only using information on American domestic assets accounts for both domestic and international stylized facts that escape consumption based models. In particular, we fail to reject the null hypothesis that the foreign currency risk premium has zero price when the instrument is the own current value of the forward premium.

The forward- and the equity-premium puzzles: two symptoms of the same illness?

We build a pricing kernel using only US domestic assets data and check whether it accounts for foreign markets stylized facts that escape consumption based models. By interpreting our stochastic discount factor as the projection of a pricing kernel from a fully specified model in the space of returns, our results indicate that a model that accounts for the behavior of domestic assets goes a long way toward accounting for the behavior of foreign assets. We address predictability issues associated with the forward premium puzzle by: i) using instruments that are known to forecast excess returns in the moments restrictions associated with Euler equations, and; ii) by pricing Lustig and Verdelhan (2007)'s foreign currency portfolios. Our results indicate that the relevant state variables that explain foreign-currency market asset prices are also the driving forces behind U.S. domestic assets behavior.

The forward- and the equity-premium puzzles: two symptoms of the same illness?

Using information on US domestic financial data only, we build a stochastic discount factor—SDF— and check whether it accounts for foreign markets stylized facts that escape consumption based models. By interpreting our SDF as the projection of a pricing kernel from a fully specified model in the space of returns, our results indicate that a model that accounts for the behavior of domestic assets goes a long way toward accounting for the behavior of foreign assets prices. We address predictability issues associated with the forward premium puzzle by: i) using instruments that are known to forecast excess returns in the moments restrictions associated with Euler equations, and; ii) by pricing Lustig and Verdelhan (2007)’s foreign currency portfolios. Our results indicate that the relevant state variables that explain foreign-currency market asset prices are also the driving forces behind U.S. domestic assets behavior.

The forward- and the equity-premium puzzles: two symptoms of the same illness?

Using information on US domestic financial data only, we build a stochastic discount factor—SDF— and check whether it accounts for foreign markets stylized facts that escape consumption based models. By interpreting our SDF as the projection of a pricing kernel from a fully specified model in the space of returns, our results indicate that a model that accounts for the behavior of domestic assets goes a long way toward accounting for the behavior of foreign assets prices. We address predictability issues associated with the forward premium puzzle by: i) using instruments that are known to forecast excess returns in the moments restrictions associated with Euler equations, and; ii) by comparing this out-of-sample results with the one obtained performing an in-sample exercise, where the return-based SDF captures sources of risk of a representative set of developed and emerging economies government bonds. Our results indicate that the relevant state variables that explain foreign-currency market asset prices are also the driving forces behind U.S. domestic assets behavior.

The forward and the equity-premium puzzles: a straightforward test of whether they are two symptoms of the same illness

We build a stochastic discount factor—SDF— using information on US domestic financial data only, and provide evidence that it accounts for foreign markets stylized facts that escape SDF’s generated by consumption based models. By interpreting our SDF as the projection of the pricing kernel from a fully specified model in the space of returns, our results indicate that a model that accounts for the behavior of domestic assets goes a long way toward accounting for the behavior of foreign assets prices. In our tests, we address predictability, a defining feature of the Forward Premium Puzzle—FPP— by using instruments that are known to forecast excess returns in the moments restrictions associated with Euler equations both in the equity and the foreign markets.

A note on the forward and the equity-premium puzzles: two symptoms of the same illness?

We build a stochastic discount factor—SDF— using information on US domestic financial data only, and provide evidence that it accounts for foreign markets stylized facts that escape SDF’s generated by consumption based models. By interpreting our SDF as the projection of the pricing kernel from a fully specified model in the space of returns, our results indicate that a model that accounts for the behavior of domestic assets goes a long way toward accounting for the behavior of foreign assets prices. In our tests, we address predictability, a defining feature of the Forward Premium Puzzle—FPP— by using instruments that are known to forecast excess returns in the moments restrictions associated with Euler equations both in the equity and the foreign markets.

The forward and the equity premium puzzles: two symptoms of the same illness?

The Forward Premium Puzzle (FPP) is how the empirical observation of a negative relation between future changes in the spot rates and the forward premium is known. Modeling this forward bias as a risk premium and under weak assumptions on the behavior of the pricing kernel, we characterize the potential bias that is present in the regressions where the FPP is observed and we identify the necessary and sufficient conditions that the pricing kernel has to satisfy to account for the predictability of exchange rate movements. Next, we estimate the pricing kernel applying two methods: i) one, du.e to Araújo et aI. (2005), that exploits the fact that the pricing kernel is a serial correlation common feature of asset prices, and ii) a traditional principal component analysis used as a procedure 1;0 generate a statistical factor modeI. Then, using on the sample and out of the sample exercises, we are able to show that the same kernel that explains the Equity Premi um Puzzle (EPP) accounts for the FPP in all our data sets. This suggests that the quest for an economic mo deI that generates a pricing kernel which solves the EPP may double its prize by simultaneously accounting for the FPP.

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all.

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all.

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all