Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapeutic principle in Parkinson's disease, but the underlying mechanisms, particularly mediating non-motor actions, remain largely enigmatic. OBJECTIVE/HYPOTHESIS: The delayed onset of neuropsychiatric actions in conjunction with first experimental evidence that STN-DBS causes disease-modifying effects prompted our investigation on how cellular plasticity in midbrain dopaminergic systems is affected by STN-DBS. METHODS: We applied unilateral or bilateral STN-DBS in two independent cohorts of 6-hydroxydopamine hemiparkinsonian rats four to eight weeks after dopaminergic lesioning to allow for the development of a stable dopaminergic dysfunction prior to DBS electrode implantation. RESULTS: After 5 weeks of STN-DBS, stimulated animals had significantly more TH+ dopaminergic neurons and fibres in both the nigrostriatal and the mesolimbic systems compared to sham controls with large effect sizes of gHedges = 1.9-3.4. DBS of the entopeduncular nucleus as the homologue of the human Globus pallidus internus did not alter the dopaminergic systems. STN-DBS effects on mesolimbic dopaminergic neurons were largely confirmed in an independent animal cohort with unilateral STN stimulation for 6 weeks or for 3 weeks followed by a 3 weeks washout period. The latter subgroup even demonstrated persistent mesolimbic dopaminergic plasticity after washout. Pilot behavioural testing showed that augmentative dopaminergic effects on the mesolimbic system by STN-DBS might translate into improvement of sensorimotor neglect. CONCLUSIONS: Our data support sustained neurorestorative effects of STN-DBS not only in the nigrostriatal but also in the mesolimbic system as a potential factor mediating long-latency neuropsychiatric effects of STN-DBS in Parkinson's disease.

Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche.

The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell-extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ-olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4-fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus-related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.

Application of the Six Sigma concept for quality assessment of different strategies in DBS surgery.

BACKGROUND: For quality analysis, we applied the Six Sigma concept to define quality indicators and their boundaries as well as to compare treatment-dependent outcome data of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson's disease (PD). METHODS: The Unified Parkinson Disease Rating Scale (UPDRS) III with on medication and on stimulation, the reduction of daily levodopa equivalence doses (LED), and the stimulation amplitude 1 year after surgery were registered. Regarding the results of the EARLYSTIM study, sigma values for applicable studies were calculated and compared. Further, the impact of perioperative conditions on patients' outcomes was analyzed. RESULTS: Forty-one studies with 2184 patients were included. The bleeding risk was 1.36%. In median, UPDRS III on/on improved by 19.9% while the LED was reduced by 45.2%. The median stimulation amplitude was 2.84 V. With the Six Sigma principle, a comparison between different centers was possible. Microelectrode recordings (MER) did not correlate with occurrence of bleedings and did not impact patient outcome. CONCLUSIONS: The Six Sigma principle can be simply used to analyze, improve and compare complex medical processes, particularly, the DBS surgery. Based on these data, higher sigma values were reached for clinical improvement in UPDRS III on/on for patients who underwent surgery in local anesthesia with intraoperative test stimulation compared to surgery in general anesthesia. However, the difference was not statistically significant. Application of MER was found to be optional with no increased bleeding risk and no improvement on patient's outcome.

Accuracy of subthalamic nucleus targeting by T2, FLAIR and SWI-3-Tesla MRI confirmed by microelectrode recordings.

BACKGROUND: Successful deep brain stimulation is mostly dependent on accurate positioning of the leads at the optimal target points. We investigated whether the identification of the subthalamic nucleus in T2-weighted 3-T MRI, fluid-attenuated inversion recovery 3-T MRI and susceptibility-weighted 3-T MRI is confirmed by intraoperative neurological microelectrode recording. METHODS: We evaluated 182 microelectrode recording leads in 21 patients with bilateral deep brain stimulation, retrospectively. Consequently, 728 electrode contact positions in T2-weighted 3-T MRI, 552 electrode contact positions in fluid-attenuated inversion recovery 3-T MRI and 490 electrode contact positions in susceptibility-weighted 3-T MRI were evaluated for a positive nucleus subthalamicus signal. RESULTS: The highest sensitivity was measured for fluid-attenuated inversion recovery 3-T MRI with 82.5 %, while the highest specificity was observed for susceptibility-weighted 3-T MRI with 90.6 %. The negative predictive value was nearly equal for susceptibility-weighted MRI and fluid-attenuated inversion recovery MRI with 87.5 % vs. 87.1 %, but the positive predictive value was higher in susceptibility-weighted 3-T MRI (86.0 %) than in the other MRI sequences. CONCLUSIONS: The susceptibility-weighted 3-T MRI-based subthalamic nucleus localization shows the best accuracy compared with T2-weighted and fluid-attenuated inversion recovery 3-T MRI. Therefore, the susceptibility-weighted 3-T MRI should be preferred for surgical planning when the operation procedure is performed under general anesthesia without microelectrode recordings.

Circadian variations influence anxiety-related behaviour, olfaction, and hedonic response in male Sprague-Dawley rats.

INTRODUCTION: Despite the acknowledged impact of circadian rhythms on various aspects of life, behavioural tests with laboratory animals often overlook alignment with their natural activity patterns. This study aims to evaluate the influence of circadian variations on the results, validity, and reliability of different behavioural tests in rats. METHODS: Three behavioural tests, the Light-Dark Box Test (LDB), assessing anxiety-related behaviour and locomotor activity; the Buried Pellet Test (BPT), revealing olfactory abilities and motivation issues; and the Sucrose Preference Test (SPT), studying the anhedonic response, were employed to encompass multiple daytime-dependent behavioural aspects in male Sprague-Dawley rats. RESULTS: Our findings underscore distinct circadian effects on locomotor activity, exploratory behaviour, olfactory acuity, motivation, and hedonic response. Notably, anxious behaviour remained unaffected by daytime conditions. Furthermore, decreased data variance was found to be correlated with conducting behavioural tests during the subjects' active phase. DISCUSSION: This study demonstrates extensive circadian influences on nearly all parameters investigated, coupled with a significant reduction in data variability during the active phase. Emphasising the importance of aligning experimental timing with rats' natural activity patterns, our results suggest that conducting tests during the active phase of the animals not only refines test sensitivity , reduces stress, and provides more representative data, but also contributes to ethical animal research (3 R) and improves test relevance. This, in turn, enhances the reliability and validity of experimental outcomes in behavioural research and promotes animal welfare.

Subthalamic nucleus but not entopeduncular nucleus deep brain stimulation enhances neurogenesis in the SVZ-olfactory bulb system of Parkinsonian rats.

Introduction: Deep brain stimulation (DBS) is a highly effective treatment option in Parkinson's disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. Methods: In our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation. Results: STN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches. Discussion: Our data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson's disease.

Effects of rasagiline on olfactory function in patients with Parkinson's disease.

BACKGROUND: Impairment of olfactory function is a well recognized nonmotor manifestation of Parkinson's disease(PD). The aim of this investigation was to determine if the MAO-B inhibitor rasagiline can improve olfaction in PD patients. METHODS: Thirty-four PD patients participated in this single-center, prospective, randomized, controlled,double-blind study. Seventeen patients were randomly assigned to rasagiline and 17 patients to placebo. Orthoand retronasal olfactory testing and recording of event related potentials were performed before and after 120 days of rasagiline versus placebo intake. RESULTS: When comparing olfactory score differences between baseline and after 120 days between the 2 groups, the level of significance was not reached. CONCLUSIONS: The primary end point of the study was not reached, and therefore, a specific effect of rasagiline on olfactory function in PD could not be demonstrated.

Anticoagulation management of myocardial infarction after deep brain stimulation: a comparison of two cases.

Deep brain stimulation (DBS) is an established treatment of various diseases, particularly used for idiopathic Parkinson's disease. Frequently, DBS patients are multimorbid and managing them may be challenging, since postoperative complications can become more likely with age. In this article, we present two cases of myocardial infarction after DBS with different therapeutic strategies. Case 1 was anticoagulated with a heparin infusion with a target partial thromboplastine time (PTT) between 50 and 60 s after the myocardial infarction and showed 3 days later, after an initial postoperative inconspicuous cranial computer tomography, an intracerebral haematoma, which was evacuated without explanting the DBS lead. Case 2 was only treated with enoxaparine 40 mg s.c. twice a day after the myocardial infarction without any further complications. Both cases benefited from the DBS with respect to the motor fluctuations, but case 1 continued to suffer from psychomotor slowdown, mild hemiparesis of the left side, visual neglect and a gaze paresis. Unfortunately, there are no established guidelines or therapy recommendations for the management of such patients. An individual therapy regime is necessary for this patient population regarding the bleeding risk, the cardial risk and the symptoms of the patient. Retrospectively, the rejection of the intravenous application of heparin in case 2 seems to be the right decision. But regarding the small number of cases, it remains still an individual therapy. Further experience will help us to develop optimal therapy strategies for this patient population.

Subthalamic nucleus deep brain stimulation does not alter growth factor expression in a rat model of stable dopaminergic deficiency.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been a highly effective treatment option for mid-to-late-stage Parkinson's disease (PD) for decades. Besides direct effects on brain networks, neuroprotective effects of STN-DBS - potentially via alterations of growth factor expression levels - have been proposed as additional mechanisms of action. OBJECTIVE: In the context of clarifying DBS mechanisms, we analyzed brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) levels in the basal ganglia, motor and parietal cortices, and dentate gyrus in an animal model of stable, severe dopaminergic deficiency. METHODS: We applied one week of continuous unilateral STN-DBS in a group of stable 6-hydroxydopamine (6-OHDA) hemiparkinsonian rats (6-OHDASTIM) in comparison to a 6-OHDA control group (6-OHDASHAM) as well as healthy controls (CTRLSTIM and CTRLSHAM). BDNF and GDNF levels were determined via ELISAs. RESULTS: The 6-OHDA lesion did not result in a persistent alteration in either BDNF or GDNF levels in a model of severe dopaminergic deficiency after completion of the dopaminergic degeneration. STN-DBS modestly increased BDNF levels in the entopeduncular nucleus, but even impaired BDNF and GDNF expression in cortical areas. CONCLUSIONS: STN-DBS does not increase growth factor expression when applied to a model of completed, severe dopaminergic deficiency in contrast to other studies in models of modest and ongoing dopaminergic degeneration. In healthy controls, STN-DBS does not influence BDNF or GDNF expression. We consider these findings relevant for clinical purposes since DBS in PD is usually applied late in the course of the disease.

Subthalamic nucleus deep brain stimulation induces nigrostriatal dopaminergic plasticity in a stable rat model of Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been a highly effective treatment option for middle to late stage Parkinson's disease for decades. Though, the underlying mechanisms of action, particularly effects on the cellular level, remain in part unclear. In the context of identifying disease-modifying effects of STN-DBS by prompting cellular plasticity in midbrain dopaminergic systems, we analyzed neuronal tyrosine hydroxylase and c-Fos expression in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). METHODS: We applied 1 week of continuous unilateral STN-DBS in a group of stable 6-hydroxydopamine (6-OHDA) hemiparkinsonian rats (STNSTIM) in comparison to a 6-OHDA control group (STNSHAM). Immunohistochemistry identified NeuN+, tyrosine hydroxylase+ and c-Fos+ cells within the SNpc and VTA. RESULTS: After 1 week, rats in the STNSTIM group had 3.5-fold more tyrosine hydroxylase+ neurons within the SNpc (P = 0.010) but not in the VTA compared to sham controls. There was no difference in basal cell activity as indicated by c-Fos expression in both midbrain dopaminergic systems. CONCLUSION: Our data support a neurorestorative effect of STN-DBS in the nigrostriatal dopaminergic system already after 7 days of continuous STN-DBS in the stable Parkinson's disease rat model without affecting basal cell activity.

Deep brain stimulation electrode modeling in rats.

Deep Brain Stimulation (DBS) is an efficacious treatment option for an increasing range of brain disorders. To enhance our knowledge about the mechanisms of action of DBS and to probe novel targets, basic research in animal models with DBS is an essential research base. Beyond nonhuman primate, pig, and mouse models, the rat is a widely used animal model for probing DBS effects in basic research. Reconstructing DBS electrode placement after surgery is crucial to associate observed effects with modulating a specific target structure. Post-mortem histology is a commonly used method for reconstructing the electrode location. In humans, however, neuroimaging-based electrode localizations have become established. For this reason, we adapt the open-source software pipeline Lead-DBS for DBS electrode localizations from humans to the rat model. We validate our localization results by inter-rater concordance and a comparison with the conventional histological method. Finally, using the open-source software pipeline OSS-DBS, we demonstrate the subject-specific simulation of the VTA and the activation of axon models aligned to pathways representing neuronal fibers, also known as the pathway activation model. Both activation models yield a characterization of the impact of DBS on the target area. Our results suggest that the proposed neuroimaging-based method can precisely localize DBS electrode placements that are essentially rater-independent and yield results comparable to the histological gold standard. The advantages of neuroimaging-based electrode localizations are the possibility of acquiring them in vivo and combining electrode reconstructions with advanced imaging metrics, such as those obtained from diffusion or functional magnetic resonance imaging (MRI). This paper introduces a freely available open-source pipeline for DBS electrode reconstructions in rats. The presented initial validation results are promising.

Adult Neural Stem Cells from Midbrain Periventricular Regions Show Limited Neurogenic Potential after Transplantation into the Hippocampal Neurogenic Niche.

The regulation of adult neural stem or progenitor cell (aNSC) proliferation and differentiation as an interplay of cell-intrinsic and local environmental cues remains in part unclear, impeding their role in putative regenerative therapies. aNSCs with all major properties of NSCs in vitro have been identified in a variety of brain regions beyond the classic neurogenic niches, including the caudal periventricular regions (PVRs) of the midbrain, though active neurogenesis is either limited or merely absent in these regions. To elucidate cell-intrinsic properties of aNSCs from various PVRs, we here examined the proliferation and early differentiation capacity of murine aNSCs from non-neurogenic midbrain PVRs (PVRMB) compared to aNSCs from the neurogenic ventricular-subventricular zone (PVRV-SVZ) 7 days after transplantation into the permissive pro-neurogenic niche of the dentate gyrus (DG) of the hippocampus in mice. An initial in vitro characterization of the transplants displayed very similar characteristics of both aNSC grafts after in vitro expansion with equal capacities of terminal differentiation into astrocytes and Tuj1+ neurons. Upon the allogenic transplantation of the respective aNSCs into the DG, PVRMB grafts showed a significantly lower graft survival and proliferative capacity compared to PVRV-SVZ transplants, whereby the latter are exclusively capable of generating new neurons. Although these differences might be-in part-related to the transplantation procedure and the short-term study design, our data strongly imply important cell-intrinsic differences between aNSCs from neurogenic compared to non-neurogenic PVRs with respect to their neurogenic potential and/or their sensitivity to neurogenic cues.

Chronic-Progressive Dopaminergic Deficiency Does Not Induce Midbrain Neurogenesis.

BACKGROUND: Consecutive adult neurogenesis is a well-known phenomenon in the ventricular-subventricular zone of the lateral wall of the lateral ventricles (V-SVZ) and has been controversially discussed in so-called "non-neurogenic" brain areas such as the periventricular regions (PVRs) of the aqueduct and the fourth ventricle. Dopamine is a known modulator of adult neural stem cell (aNSC) proliferation and dopaminergic neurogenesis in the olfactory bulb, though a possible interplay between local dopaminergic neurodegeneration and induction of aNSC proliferation in mid/hindbrain PVRs is currently enigmatic. OBJECTIVE/HYPOTHESIS: To analyze the influence of chronic-progressive dopaminergic neurodegeneration on both consecutive adult neurogenesis in the PVRs of the V-SVZ and mid/hindbrain aNSCs in two mechanistically different transgenic animal models of Parkinson´s disease (PD). METHODS: We used Thy1-m[A30P]h α synuclein mice and Leu9'Ser hypersensitive α4* nAChR mice to assess the influence of midbrain dopaminergic neuronal loss on neurogenic activity in the PVRs of the V-SVZ, the aqueduct and the fourth ventricle. RESULTS: In both animal models, overall proliferative activity in the V-SVZ was not altered, though the proportion of B2/activated B1 cells on all proliferating cells was reduced in the V-SVZ in Leu9'Ser hypersensitive α4* nAChR mice. Putative aNSCs in the mid/hindbrain PVRs are known to be quiescent in vivo in healthy controls, and dopaminergic deficiency did not induce proliferative activity in these regions in both disease models. CONCLUSIONS: Our data do not support an activation of endogenous aNSCs in mid/hindbrain PVRs after local dopaminergic neurodegeneration. Spontaneous endogenous regeneration of dopaminergic cell loss through resident aNSCs is therefore unlikely.

The software defined implantable modular platform (STELLA) for preclinical deep brain stimulation research in rodents.

Context.Long-term deep brain stimulation (DBS) studies in rodents are of crucial importance for research progress in this field. However, most stimulation devices require jackets or large head-mounted systems which severely affect mobility and general welfare influencing animals' behavior.Objective.To develop a preclinical neurostimulation implant system for long-term DBS research in small animal models.Approach.We propose a low-cost dual-channel DBS implant called software defined implantable platform (STELLA) with a printed circuit board size of Ø13 × 3.3 mm, weight of 0.6 g and current consumption of 7.6µA/3.1 V combined with an epoxy resin-based encapsulation method.Main results.STELLA delivers charge-balanced and configurable current pulses with widely used commercial electrodes. Whilein vitrostudies demonstrate at least 12 weeks of error-free stimulation using a CR1225 battery, our calculations predict a battery lifetime of up to 3 years using a CR2032. Exemplary application for DBS of the subthalamic nucleus in adult rats demonstrates that fully-implanted STELLA neurostimulators are very well-tolerated over 42 days without relevant stress after the early postoperative phase resulting in normal animal behavior. Encapsulation, external control and monitoring of function proved to be feasible. Stimulation with standard parameters elicited c-Fos expression by subthalamic neurons demonstrating biologically active function of STELLA.Significance.We developed a fully implantable, scalable and reliable DBS device that meets the urgent need for reverse translational research on DBS in freely moving rodent disease models including sensitive behavioral experiments. We thus add an important technology for animal research according to 'The Principle of Humane Experimental Technique'-replacement, reduction and refinement (3R). All hardware, software and additional materials are available under an open source license.

Rostro-caudal gradual loss of cellular diversity within the periventricular regions of the ventricular system.

Neurogenesis occurs constitutively within the periventricular region (PVR) of the lateral ventricles (LV) of the adult mammalian brain. The occurrence of adult neurogenesis within the PVR outside the neurogenic niche of the LV remains controversial, but neural stem cells can be isolated from PVR of the whole ventricular system. The histological basis of this phenomenon including the regional differences of cellular phenotypes within the PVRs is still enigmatic. The occurrence of neurogenesis or manipulable progenitor cells in caudal parts of the adult brain is however one prerequisite for orthotopic regenerative approaches in Parkinson's disease (PD) and other disorders of the midbrain/brainstem. Using quantitative immunohistochemical techniques and electron microscopy, we found a rostro-caudal gradual loss of cellular diversity within the PVR throughout the whole ventricular axis with loss of transit amplifying epidermal growth factor-receptor(+) type C cells in all parts caudal to the LV, a gradual reduction from rostral to caudal of both stem cells (type B cells or astrocytes) without signs of proliferation outside the PVR of the LV as well as neuroblasts-like cells (polysialylated neural cell adhesion molecule [PSA-NCAM](+), but doublecortin negative cells) with a different morphology compared with neuroblasts of the PVR of the LV. Electron microscopy confirmed these immunohistochemical data. The proportion of Nestin(+)/CD24(+) cells and Nestin(+)/S100beta(+) ependymal cells were consecutively increased in the PVR from rostral to caudal, and ultrastructural analysis showed a region-specific morphology with darker cytoplasm with occasional large lipid droplets as well as indented nuclei within the caudal PVRs. The strong correlation of neuroblast-like cells with the number of neurosphere-forming cells suggests that a quiescent subtype of PSA-NCAM(+) cells might be a source of neurosphere-forming cells. We did not find any evidence for neurogenesis or the occurrence of neuroprogenitors within the substantia nigra or other parts of the midbrain/brainstem outside the PVR. Our data provide the histological framework for future studies on orthotopic regenerative approaches in PD by recruiting endogenous predopaminergic progenitors from the midbrain PVR.

Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain.

The major catecholamines-dopamine (DA) and norepinephrine (NE)-are not only involved in synaptic communication but also act as important trophic factors and might ultimately be involved in mammalian brain development. The catecholaminergic innervation of neurogenic regions of the developing brain and its putative relationship to neurogenesis is thus of pivotal interest. We here determined DA and NE innervation around the ventricular/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from embryonic day 14.5 (E14.5), E16.5, and E19.5 until postnatal day zero (P0) by histological evaluation and HPLC with electrochemical detection. We correlated these data with the proliferation capacity of the respective regions by quantification of MCM2+ cells. During development, VZ/SVZ catecholamine levels dramatically increased between E16.5 and P0 with DA levels increasing in forebrain VZ/SVZ bordering the lateral ventricles and NE levels raising in midbrain/hindbrain VZ/SVZ bordering the third ventricle, the aqueduct, and the fourth ventricle. Conversely, proliferating MCM2+ cell counts dropped between E16.5 and E19.5 with a special focus on all VZ/SVZs outside the lateral ventricles. We detected an inverse strong negative correlation of the proliferation capacity in the periventricular neurogenic regions (log-transformed MCM2+ cell counts) with their NE levels (r = -0.932; p < 0.001), but not their DA levels (r = 0.440; p = 0.051) suggesting putative inhibitory effects of NE on cell proliferation within the periventricular regions during mouse brain development. Our data provide the first framework for further demandable studies on the functional importance of catecholamines, particularly NE, in regulating neural stem/progenitor cell proliferation and differentiation during mammalian brain development.

Sleep Disturbances and Sleep Disordered Breathing Impair Cognitive Performance in Parkinson's Disease.

BACKGROUND: Sleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson's disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance. OBJECTIVE: This post hoc analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD. METHODS: Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients' subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated. RESULTS: We did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, P = 0.020, unpaired two-sided t-test). CONCLUSION: Sleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.

Timing and Kinetics of Nonmotor Fluctuations in Advanced Parkinson's Disease.

BACKGROUND: Nonmotor symptoms (NMS) are known to fluctuate together with motor oscillations in advanced PD, but their timing and kinetics remains enigmatic. OBJECTIVE: To evaluate timing and kinetics of NMS fluctuations. METHODS: Analysis of diary data from 17 fluctuating PD patients. Diaries were completed by rating NMS as absent (defined herein as NMS On state) or present (NMS Off state) and motor function for every hour for 5 consecutive days. Timing and kinetics were analyzed by synchronizing motor Off periods and subsequent cross-classification of NMS Off periods for each motor Off hour into 2×2 contingency tables. RESULTS: We found clear temporal connections of NMS Off periods with motor Off periods only for anxiety/depression, concentration/attention deficiency and bladder urgency. Psychiatric NMS Off periods had a longer duration (median: 3-4 hours) compared to motor Off periods (2 hours; P < 0.05, Mann-Whitney U-test). CONCLUSIONS: Our data on timing and kinetics of NMS fluctuations show close temporal connection with motor Off periods only for mood and cognitive symptoms. Variances in both timing and/or kinetics of NMS fluctuations might explain both the weak/absent correlations of NMS and motor symptom severity in fluctuating patients and the rather low rates of simultaneous switches between On and Off states for NMS and motor function.

Accelerated Age-Dependent Hippocampal Volume Loss in Parkinson Disease With Mild Cognitive Impairment.

BACKGROUND: Patients with Parkinson disease are at high risk of developing dementia. During the course of the disease, a substantial number of patients will experience a cognitive decline, indicating the dynamics of the underlying neuropathology. Magnetic resonance imaging (MRI) has become increasingly useful for identifying structural characteristics in radiological brain anatomy existing prior to clinical symptoms. Whether these changes reflect pathology, whether they are aging related, or both often remains unclear. We hypothesized that aging-associated brain structural changes would be more pronounced in the hippocampal region among patients with Parkinson disease having mild cognitive deficits relative to cognitively unimpaired patients. METHODS: Using MRI, we investigated 30 cognitively healthy patients with Parkinson disease and 33 patients with nondemented Parkinson disease having mild cognitive impairment. All participants underwent structural MRI scanning and extensive clinical and neuropsychological assessments. RESULTS: Irrespective of the study participants' cognitive status, older age was associated with reduced cortical thickness in various neocortical regions. Having mild cognitive impairment was not associated with an increased rate of cortical thinning or volume loss in these regions, except in the hippocampus bilaterally. CONCLUSION: Patients with Parkinson disease having mild cognitive impairment show an accelerated age-dependent hippocampal volume loss when compared with cognitively healthy patients with Parkinson disease. This may indicate pathological processes in a key region for memory functioning in patients with Parkinson disease at risk of developing dementia. Structural MRI of the hippocampal region could potentially contribute to identifying patients who should receive early treatment aimed at delaying the clinical onset of dementia.

Assessment of Nonmotor Fluctuations Using a Diary in Advanced Parkinson's disease.

BACKGROUND: Since previous studies aimed to study nonmotor symptom (NMS) fluctuations in direct conjunction with motor oscillations, there are no data available on the temporal context of NMS fluctuations and motor oscillations in advanced Parkinson's disease (PD). OBJECTIVE: To evaluate circadian patterns and temporal connections of NMS and motor fluctuations in PD. METHODS: 15 controls, 17 non-fluctuating and 15 fluctuating PD patients completed two diaries by rating 4 key psychiatric (anxiety, depressive mood, inner restlessness, concentration/attention deficits), fatigue and 4 autonomic NMS (excessive sweating, sialorrhea, bladder urgency, dizziness) absent or present and motor function (Off, On with/without dyskinesia, and asleep) for every hour for 5 consecutive days. RESULTS: NMS Off state hours (hours with NMS rated as present) were less frequent compared to motor Off state hours and NMS On-Off-switches were less prevalent compared to those of the motor state. Off time and number of On-Off-switches of psychiatric NMS were moderately correlated with motor Off time and number of motor On-Off switches on the individual patient level. Changes in NMS state occurred largely independent of changes in motor states with concordance rates of only 26-43% of all NMS changes for psychiatric and 7-17% for autonomic NMS. In controls and non-fluctuating PD patients, there were no NMS state switches in concordance to motor state switches. CONCLUSION: We provide first data on the temporal context of NMS fluctuations showing similar frequencies of psychiatric NMS Off, fatigue Off and motor Off times as well as their On-Off-fluctuations, but low concordance rates of NMS with motor On-Off-state switches. We found no evidence for NMS fluctuations in non-fluctuating PD patients. Our data implicate similar fluctuation patterns of mood NMS and motor function without close timing and/or different kinetics.