Deep brain stimulation of the subthalamic nucleus restores spatial reversal learning in patients with Parkinson's disease.

Spatial learning and navigation are supported by distinct memory systems in the human brain such as the hippocampus-based navigational system and the striatum-cortex-based system involved in motor sequence, habit and reversal learning. Here, we studied the role of subthalamic circuits in hippocampus-associated spatial memory and striatal-associated spatial reversal learning formation in patients with Parkinson's disease, who underwent a deep brain stimulation of the subthalamic nucleus. Deep brain stimulation patients (Parkinson's disease-subthalamic nucleus: n = 26) and healthy subjects (n = 15) were tested in a novel experimental spatial memory task based on the Morris water maze that assesses both hippocampal place memory as well as spatial reversal learning. All subjects were trained to navigate to a distinct spatial location hidden within the virtual environment during 16 learning trials in a subthalamic nucleus Stim-On condition. Patients were then randomized into two groups with either a deep brain stimulation On or Off condition. Four hours later, subjects were retested in a delayed recall and reversal learning condition. The reversal learning was realized with a new hidden location that should be memorized during six consecutive trials. The performance was measured by means of an index indicating the improvement during the reversal learning. In the delayed recall condition, neither patients, healthy subjects nor the deep brain stimulation On- versus Off groups showed a difference in place memory performance of the former trained location. In the reversal learning condition, healthy subjects (reversal index 2.0) and patients in the deep brain stimulation On condition (reversal index 1.6) showed a significant improvement. However, patients in the deep brain stimulation Off condition (reversal index 1.1) performed significantly worse and did not improve. There were no differences between all groups in a final visual guided navigation task with a visible target. These results suggest that deep brain stimulation of subthalamic nucleus restores spatial reversal learning in a virtual navigation task in patients with Parkinson's disease and gives insight into the neuromodulation effects on cognition of subthalamic circuits in Parkinson's disease.

Propofol Reversibly Attenuates Short-Range Microstate Ordering and 20 Hz Microstate Oscillations.

Microstate sequences summarize the changing voltage patterns measured by electroencephalography, using a clustering approach to reduce the high dimensionality of the underlying data. A common approach is to restrict the pattern matching step to local maxima of the global field power (GFP) and to interpolate the microstate fit in between. In this study, we investigate how the anesthetic propofol affects microstate sequence periodicity and predictability, and how these metrics are changed by interpolation. We performed two frequency analyses on microstate sequences, one based on time-lagged mutual information, the other based on Fourier transform methodology, and quantified the effects of interpolation. Resting-state microstate sequences had a 20 Hz frequency peak related to dominant 10 Hz (alpha) rhythms, and the Fourier approach demonstrated that all five microstate classes followed this frequency. The 20 Hz periodicity was reversibly attenuated under moderate propofol sedation, as shown by mutual information and Fourier analysis. Characteristic microstate frequencies could only be observed in non-interpolated microstate sequences and were masked by smoothing effects of interpolation. Information-theoretic analysis revealed faster microstate dynamics and larger entropy rates under propofol, whereas Shannon entropy did not change significantly. In moderate sedation, active information storage decreased for non-interpolated sequences. Signatures of non-equilibrium dynamics were observed in non-interpolated sequences, but no changes were observed between sedation levels. All changes occurred while subjects were able to perform an auditory perception task. In summary, we show that low dose propofol reversibly increases the randomness of microstate sequences and attenuates microstate oscillations without correlation to cognitive task performance. Microstate dynamics between GFP peaks reflect physiological processes that are not accessible in interpolated sequences.

Complexity Measures for EEG Microstate Sequences: Concepts and Algorithms.

EEG microstate sequence analysis quantifies properties of ongoing brain electrical activity which is known to exhibit complex dynamics across many time scales. In this report we review recent developments in quantifying microstate sequence complexity, we classify these approaches with regard to different complexity concepts, and we evaluate excess entropy as a yet unexplored quantity in microstate research. We determined the quantities entropy rate, excess entropy, Lempel-Ziv complexity (LZC), and Hurst exponents on Potts model data, a discrete statistical mechanics model with a temperature-controlled phase transition. We then applied the same techniques to EEG microstate sequences from wakefulness and non-REM sleep stages and used first-order Markov surrogate data to determine which time scales contributed to the different complexity measures. We demonstrate that entropy rate and LZC measure the Kolmogorov complexity (randomness) of microstate sequences, whereas excess entropy and Hurst exponents describe statistical complexity which attains its maximum at intermediate levels of randomness. We confirmed the equivalence of entropy rate and LZC when the LZ-76 algorithm is used, a result previously reported for neural spike train analysis (Amigó et al., Neural Comput 16:717-736, https://doi.org/10.1162/089976604322860677 , 2004). Surrogate data analyses prove that entropy-based quantities and LZC focus on short-range temporal correlations, whereas Hurst exponents include short and long time scales. Sleep data analysis reveals that deeper sleep stages are accompanied by a decrease in Kolmogorov complexity and an increase in statistical complexity. Microstate jump sequences, where duplicate states have been removed, show higher randomness, lower statistical complexity, and no long-range correlations. Regarding the practical use of these methods, we suggest that LZC can be used as an efficient entropy rate estimator that avoids the estimation of joint entropies, whereas entropy rate estimation via joint entropies has the advantage of providing excess entropy as the second parameter of the same linear fit. We conclude that metrics of statistical complexity are a useful addition to microstate analysis and address a complexity concept that is not yet covered by existing microstate algorithms while being actively explored in other areas of brain research.

Grey matter correlates of dystonic soft signs in essential tremor.

BACKGROUND: Questionable signs of dystonia are a common finding in patients with essential tremor (ET). Brain structural alterations in ET patients plus dystonic soft signs (ET + ds) in comparison to ET patients without dystonic soft signs (ET-ds) or patients with tremor associated with manifest dystonia (TAWD) have not been examined yet. Therefore, our study aims to explore alterations of brain grey matter in patients with ET + ds. METHODS: A total of 68 elderly patients with ET-ds (n = 32), ET + ds (n = 20) or idiopathic cervical dystonia with dystonia associated action tremor of the upper limbs (TAWD, n = 16) and 42 age-matched healthy controls underwent a clinical and electrophysiological assessment and 3T MRI. For grey matter alterations T1 MRI images were analysed by voxel-based morphometry. Additionally, regression analyses with clinical parameters (tremor frequency, severity and disease duration) were performed. RESULTS: VBM showed a significant increase of grey matter in the right lentiform nucleus in ET + ds and TAWD compared to HC and ET-ds. Further, an increase of cortical grey matter in the middle frontal gyrus in ET + ds was shown. The hypertrophy of the lentiform nucleus in ET + ds was correlated with disease severity and duration. CONCLUSION: Patients with ET + ds showed grey matter brain structural alterations similar to TAWD. Our findings suggest an involvement of the basal ganglia-cortical loop in ET + ds which may indicate a pathophysiological similarity with TAWD rather than ET.

Neural Correlates of Executed Compared to Imagined Writing and Drawing Movements: A Functional Magnetic Resonance Imaging Study.

Objective: In this study we used functional magnetic resonance imaging (fMRI) to investigate whether motor imagery (MI) of handwriting and circle drawing activates a similar handwriting network as writing and drawing itself. Methods: Eighteen healthy right-handed participants wrote the German word "Wellen" and drew continuously circles in a sitting (vertical position) and lying position (horizontal position) to capture kinematic handwriting parameters such as velocity, pressure and regularity of hand movements. Afterward, they performed the same tasks during fMRI in a MI and an executed condition. Results: The kinematic analysis revealed a general correlation of handwriting parameters during sitting and lying except of pen pressure during drawing. Writing compared to imagined writing was accompanied by an increased activity of the ipsilateral cerebellum and the contralateral sensorimotor cortex. Executed compared to imagined drawing revealed elevated activity of a fronto-parieto-temporal network. By contrasting writing and drawing directly, executed writing induced an enhanced activation of the left somatosensory and premotor area. The comparison of the MI of these tasks revealed a higher involvement of occipital activation during imagined writing. Conclusion: The kinematic results pointed to a high comparability of writing in a vertical and horizontal position. Overall, we observed highly overlapping cortical activity except of a higher involvement of motor control areas during motor execution. The sparse difference between writing and drawing can be explained by highly automatized writing in healthy individuals.

The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Functional Neural Networks in Writer's Cramp as Determined by Graph-Theoretical Analysis.

Dystonia, a debilitating neurological movement disorder, is characterized by involuntary muscle contractions and develops from a complex pathophysiology. Graph theoretical analysis approaches have been employed to investigate functional network changes in patients with different forms of dystonia. In this study, we aimed to characterize the abnormal brain connectivity underlying writer's cramp, a focal hand dystonia. To this end, we examined functional magnetic resonance scans of 20 writer's cramp patients (11 females/nine males) and 26 healthy controls (10 females/16 males) performing a sequential finger tapping task with their non-dominant (and for patients non-dystonic) hand. Functional connectivity matrices were used to determine group averaged brain networks. Our data suggest that in their neuronal network writer's cramp patients recruited fewer regions that were functionally more segregated. However, this did not impair the network's efficiency for information transfer. A hub analysis revealed alterations in communication patterns of the primary motor cortex, the thalamus and the cerebellum. As we did not observe any differences in motor outcome between groups, we assume that these network changes constitute compensatory rerouting within the patient network. In a secondary analysis, we compared patients with simple writer's cramp (only affecting the hand while writing) and those with complex writer's cramp (affecting the hand also during other fine motor tasks). We found abnormal cerebellar connectivity in the simple writer's cramp group, which was less prominent in complex writer's cramp. Our preliminary findings suggest that longitudinal research concerning cerebellar connectivity during WC progression could provide insight on early compensatory mechanisms in WC.

Abnormal effective connectivity in the sensory network in writer's cramp.

BACKGROUND: Writer's cramp (WC), a task specific form of dystonia, is considered to be a motor network disorder, but abnormal sensory tactile processing has also been acknowledged. The sensory spatial discrimination threshold (SDT) can be determined with a spatial acuity test (JVP domes). In addition to increased SDT, patients with WC exhibited dysfunctional sensory processing in the sensory cortex, insula, basal ganglia and cerebellum in a functional magnetic resonance imaging (fMRI) study while performing the spatial acuity test. OBJECTIVES: To assess whether effective connectivity (EC) in the sensory network including cortical, basal ganglia, thalamic and cerebellar regions of interest in WC patients is abnormal. METHODS: We used fMRI and applied a block design, while 19 WC patients and 13 age-matched healthy controls performed a spatial discrimination task. Before we assessed EC using dynamic causal modelling, we compared three model structures based on the current literature. We enclosed regions of interest that are established for sensory processing during right hand stimulation: Left thalamus, somatosensory, parietal and insular cortex, posterior putamen, and right cerebellum. RESULTS: The EC analysis revealed task-dependent decreased unidirectional connectivity between the insula and the posterior putamen. The connectivity involving the primary sensory cortex, parietal cortex and cerebellum were not abnormal in WC. The two groups showed no differences in their behavioural data. CONCLUSIONS: Perception and integration of sensory information requires the exchange of information between the insula cortex and the putamen, a sensory process that was disturbed in WC patients.

Memory enhancement by multidomain group cognitive training in patients with Parkinson's disease and mild cognitive impairment: long-term effects of a multicenter randomized controlled trial.

BACKGROUND: Meta-analyses indicate positive effects of cognitive training (CT) in patients with Parkinson's disease (PD), however, most previous studies had small sample sizes and did not evaluate long-term follow-up. Therefore, a multicenter randomized controlled, single-blinded trial (Train-ParC study) was conducted to examine CT effects in PD patients with mild cognitive impairment (PD-MCI). Immediately after CT, an enhancement of executive functions was demonstrated. Here, we present the long-term results 6 and 12 months after CT. METHODS: At baseline, 64 PD-MCI patients were randomized to a multidomain CT group (n = 33) or to a low-intensity physical activity training control group (PT) (n = 31). Both interventions included 90 min training sessions twice a week for 6 weeks. 54 patients completed the 6 months (CT: n = 28, PT: n = 26) and 49 patients the 12 months follow-up assessment (CT: n = 25, PT: n = 24). Primary study outcomes were memory and executive functioning composite scores. Mixed repeated measures ANOVAs, post-hoc t tests and multiple regression analyses were conducted. RESULTS: We found a significant time x group interaction effect for the memory composite score (p = 0.006, η2 = 0.214), but not for the executive composite score (p = 0.967, η2 = 0.002). Post-hoc t tests revealed significant verbal and nonverbal memory improvements from pre-intervention to 6 months, but not to 12 months follow-up assessment in the CT group. No significant predictors were found for predicting memory improvement after CT. CONCLUSIONS: This study provides Class 1 evidence that multidomain CT enhances memory functioning in PD-MCI after 6 months but not after 12 months, whereas executive functioning did not change in the long-term. CLINICAL TRIAL REGISTRATION: German Clinical Trials Register (ID: DRKS00010186), 21.3.2016 (The study registration is outlined as retrospective due to an administrative delay. The first patient was enrolled three months after the registration process was started. A formal confirmation of this process from the German Clinical Trials Register can be obtained from the authors.).

Screen Fast, Screen Faster: A Pilot Study to Screen for Depressive Symptoms Using the Beck Depression Inventory Fast Screen in Parkinson's Disease With Mild Cognitive Impairment.

Objective: Depressive symptoms have a high prevalence in patients with Parkinson's disease (PD) and are associated with cognitive dysfunction. Especially in PD with mild cognitive impairment (MCI), a time-efficient and valid instrument for the assessment of depression primarily focusing on psychological symptoms and disregarding confounding somatic symptoms is needed. We performed an examination of the psychometric properties of the Beck Depression Inventory II (BDI-II) and the Beck Depression Inventory Fast Screen (BDI-FS). Methods: The sample consisted of 64 patients [22 females and 42 males, mean age: 67.27 years (SD = 7.32)]. Depressive symptoms were measured in a cohort of PD patients with MCI. For the BDI-II and BDI-FS the psychometric concepts of internal consistency, convergent validity and diagnostic agreement were assessed. Results: Patients gave higher ratings on test items addressing somatic symptoms than those addressing non-somatic ones. The correlation between the absolute total scores of the BDI-II and the BDI-FS was significant (r = 0.91, p < 0.001), which indicated convergent validity. The Cronbach's alpha values indicated adequate internal consistencies for both measures (BDI-II: 0.84; BDI-FS: 0.78). There was a higher than chance level agreement of diagnoses of the two questionnaires, measured by Cohen's kappa (0.58, p < 0.001). The agreements between previous diagnosis of depression and the diagnoses of the BDI-II/BDI-FS were also significantly higher than chance level (BDI-II: 0.34, p = 0.007, BDI-FS: 0.39, p = 0.002). Additional AUC analysis across different cutoffs showed that performance of BDI-FS was better than BDI-II, supporting the observation of an equivalent or better performance of BDI-FS than BDI-II. Importantly, AUC analysis confirmed that a cutoff = 4 for BDI-FS was suitable in the considered sample of patients with PD-MCI. Discussion: In a cohort of PD-MCI, the BDI-FS demonstrates adequate psychometric properties in comparison to the BDI-II and can be used as a screening measure for assessing depression in cognitively impaired PD patients, focusing solely on psychological symptoms. Still, further research is needed to validate this instrument.