Substantia Nigra Pars Reticulate Research Articles

Histogram analysis of diffusion kurtosis imaging of deep brain nuclei in Parkinson's disease with different motor subtypes

To evaluate the diagnostic and differential efficacy of diffusion kurtosis imaging (DKI) histogram analysis for different motor subtypes of Parkinson's disease (PD). Seventy PD patients including 40 with postural instability and gait disorder (PIGD) and 30 with tremor-dominant (TD) and 36 healthy controls (HC) were enrolled prospectively and underwent MRI examinations. The regions of interest (ROI) in the deep brain nuclei were delineated and features were extracted on the map of mean kurtosis (MK), axial kurtosis (Ka), and radial kurtosis (Kr), respectively. The differences in histogram features between PD patients and HC and between patients with PIGD and TD were compared. The areas under the curve (AUCs) were calculated to evaluate the diagnostic efficacy of all histogram features. The correlations between histogram features and clinical indicators were evaluated. Some DKI histogram features were significantly different between PD patients and HC, and also different between patients with PIGD and TD (all p<0.05). MK of the substantia nigra pars reticulate (SNprkurtosis), Ka of the substantia nigra pars compacta (SNpc) 50 percentile (SNpcP50), and Kr of SNpc 90th percentile showed the highest AUC for distinguishing patients with PIGD from HC. MK-SNpc 10th percentile, Ka-SNpc 25th percentile, and Kr of the head of the caudate nucleus (CN) 90th percentile had the highest AUC for distinguishing patients with TD from HC. MK of the putamen 10th percentile combined with Ka of the bilateral red nucleus RNkurtosis yielded the highest diagnostic performance with an AUC of 0.762 for distinguishing patients with PIGD from TD. Certain DKI histogram features were correlated with Hoehn-Yahr (H&Y) stage, Mini Mental State Examination (MMSE) score, tremor score, and PIGD score (all p<0.05). DKI histogram analysis was useful to diagnose and discriminate different motor subtypes of PD. Certain DKI histogram features correlated with clinical indicators.

People With Parkinson's Disease and Freezing of Gait Show Abnormal Low Frequency Activity of Antagonistic Leg Muscles.

ObjectiveFreezing of gait is detrimental to patients with idiopathic Parkinson’s disease (PD). Its pathophysiology represents a multilevel failure of motor processing in the cortical, subcortical, and brainstem circuits, ultimately resulting in ineffective motor output of the spinal pattern generator. Electrophysiological studies pointed to abnormalities of oscillatory activity in freezers that covered a broad frequency range including the theta, alpha, and beta bands. We explored muscular frequency domain activity with respect to freezing, and used deep brain stimulation to modulate these rhythms thereby evaluating the supraspinal contributions to spinal motor neuron activity.MethodsWe analyzed 9 PD freezers and 16 healthy controls (HC). We studied the patients after overnight withdrawal of dopaminergic medication with stimulation off, stimulation of the subthalamic nucleus (STN-DBSonly) or the substantia nigra pars reticulate (SNr-DBSonly), respectively. Patients performed a walking paradigm passing a narrow obstacle. We analyzed the frequency-domain spectra of the tibialis anterior (TA) and gastrocnemius (GA) muscles in ‘regular gait’ and during the ‘freezing’ episodes.ResultsIn stimulation off, PD freezers showed increased muscle activity of the alpha and low-beta band compared to HC in both TA and GA. This activity increase was present during straight walking and during the freezes to similar extent. STN- but not SNr-DBS decreased this activity and paralleled the clinical improvement of freezing.ConclusionWe found increased muscle activation of the alpha and lower beta band in PD freezers compared to HC, and this was attenuated with STN-DBS. Future studies may use combined recordings of local field potentials, electroencephalography (EEG), and electromyography (EMG) to interrogate the supraspinal circuit mechanisms of the pathological activation pattern of the spinal pattern generator.

Diffusion kurtosis imaging characteristics of brain gray matter nucleus microstructure in Parkinson's disease with different movement disorder subtypes

Objective To investigate the difference in the microstructure of gray matter nucleus in different movement subtypes of Parkinson’s disease (PD) by diffusion kurtosis imaging (DKI) technique, and to analyze the correlation with clinical manifestations. Methods Ninety-seven patients with PD and 83 healthy controls performed conventional MRI sequence and DKI sequence scan. The PD patients were classified into gait disorder subtype (PIGD, n=57) and tremor dominant subtype (TD, n=40)subtypes according to motor symptoms. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), radial diffusivity(Dr), mean kurtosis (MK), axial kurtosis (Ka) and radial kurtosis (Dr) maps and data were generated by software after processing. DKI was performed for all subjects and data was collected from different brain regions in both hemispheres, including red nucleus(RN), substantia nigra pars reticulate(SNr), substantia nigra pars compacta(SNc), putamen(PUT), globus pallidus(GP), head of caudate nucleus (CN)and thalamus(THA). Results TD showed a higher MMSE score(P=0.019), but lower modified Hoehn-Yahr score than that in PIGD (P 0.05). Moreover, there was no significant correlation between DKI value and disease duration, MMSE score or Hoehn-Yahr scale (P>0.05) in TD and PIGD. Conclusion There is heterogeneity of clinical symptoms between these two subgroups of PD. DKI can quantify the microstructural changes of grey matter nucleus in different type PD patient. Key words: Parkinson's disease; Movement disorder subtypes; Diffusion kurtosis imaging; Heterogeneity

Targeted upregulation of uncoupling protein 2 within the basal ganglia output structure ameliorates dyskinesia after severe liver failure

Impaired motor function, due to the dysfunction of the basal ganglia, is the most common syndrome of hepatic encephalopathy (HE), and its etiology remains poorly understood. Neural oxidative stress is shown to be the major cellular defects contributing to HE pathogenesis. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in neuroprotection in several neurological disorders. We explored the neuroprotective role of UCP2 within the substantia nigra pars reticulate (SNr), the output structure of the basal ganglia, in HE. The toxin thioacetamide (TAA) induced HE mice showed hypolocomotion, which was associated with decreased ATP levels and loss of antioxidant substances SOD and GSH within the SNr. Stable overexpression of UCP2 via AAV-UCP2 under the control of the UCP2 promoter in bilateral SNr preserved local ATP level, increased antioxidant substances, and ameliorated locomotion defects after severe liver failure. Contrary to UCP2 overexpression, targeted knockdown of UCP2 within bilateral SNr via AAV-UCP2 shRNA exacerbated the impaired mitochondrial dysfunction and hypokinesia in HE mice. The modulatory effects of UCP2 was due to mediation of K+-Cl− cotransporter-2 (KCC2) expression on GABAergic neurons of SNr. Taken together, our results demonstrate that UCP2 exerts a neural protective role at the subcortical level by increasing the resistance of neurons to oxidative stress, which may offer a novel therapeutic target for the treatment of motor dysfunction diseases.

A Review of the Pedunculopontine Nucleus in Parkinson's Disease.

The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.

EP 3. Nigral stimulation for freezing of gait: Clinico-anatomic correlations

Objective In this study we aimed to address the impact of electrode localization in idiopathic Parkinson’s disease patients (iPD) with combined stimulation of the subthalamic nucleus (STN) and substantia nigra pars reticulate (SNr) and freezing of gait (FOG). Background FOG presents as disabling and often resistant motor symptom in iPD. First evidence for an effect of additive SNr stimulation on otherwise resistant FOG came from a recent randomized controlled trial ( Weiss et al., 2013 ) and translates now into a multicenter German-wide trial. Methods Ten patients with advanced iPD and combined STN + SNr stimulation were followed over a period of 12 months with regular visits at start (STN stimulation) as derived from the standard STN scores of our cross-over study ( Weiss et al., 2013) , and 6 week (STN+SNr stimulation) and 12 month (STN + SNr stimulation) follow-up as derived from our observation open-label study. MCP based coordinates of active SNr contacts were determined with Medtronic Optivise TM system and FOG was assessed by the Freezing Assessment Course (FAC). The difference of the FAC-score between 6 weeks STN+SNr to STN and 12 months STN + SNr to STN stimulation were built. The coordinates of active SNr contacts were correlated with therapeutic effects of combined STN+SNr stimulation on FAC. Results Improvement of FOG with combined STN+SNr stimulation was correlated with more medial positions of the left active SNr contact at six week follow-up. The left SNr contact was located more medially in strong responders ( n = 5) compared to mild or non-responders (FAC improvement n = 5) at six week ( n = 10). There was no correlation of electrode laterality and FOG impairment with STN stimulation excluding confounding of our findings by stratification. No correlation of electrode position and FOG improvement was identified at 12 months ( n = 8, two drop-outs). Conclusion The results may point to superior treatment effects if the active SNr electrode is placed more medially. However, the findings have to be considered with caution and unilateral clinical test stimulations and correlations with the clinical effect on FOG have to give closer insight in future.

Direct and indirect pathways of the basal ganglia: opponents or collaborators?

Direct and indirect pathways of the basal ganglia: opponents or collaborators?

Cell cycle regulation of DNA polymerase beta in rotenone-based Parkinson's disease models.

In Parkinson's disease (PD), neuronal cells undergo mitotic catastrophe and endoreduplication prior to cell death; however, the regulatory mechanisms remain to be defined. In this study, we investigated cell cycle regulation of DNA polymerase β (poly β) in rotenone-based dopaminergic cellular and animal models. Incubation with a low concentration (0.25 µM) of rotenone for 1.5 to 7 days resulted in a flattened cell body and decreased DNA replication during S phase, whereas a high concentration (2 µM) of rotenone exposure resulted in enlarged, multi-nucleated cells and converted the mitotic cycle into endoreduplication. Consistently, DNA poly β, which is mainly involved in DNA repair synthesis, was upregulated to a high level following exposure to 2 µM rotenone. The abrogation of DNA poly β by siRNA transfection or dideoxycytidine (DDC) treatment attenuated the rotenone-induced endoreduplication. The cell cycle was reactivated in cyclin D-expressing dopaminergic neurons from the substantia nigra (SN) of rats following stereotactic (ST) infusion of rotenone. Increased DNA poly β expression was observed in the substantia nigra pars compacta (SNc) and the substantia nigra pars reticulate (SNr) of rotenone-treated rats. Collectively, in the in vitro model of rotenone-induced mitotic catastrophe, the overexpression of DNA poly β promotes endoreduplication; in the in vivo model, the upregulation of DNA poly β and cell cycle reentry were also observed in the adult rat substantia nigra. Therefore, the cell cycle regulation of DNA poly β may be involved in the pathological processes of PD, which results in the induction of endoreduplication.

A quantitative comparison of basal ganglia neuronal activities of normal and Parkinson's disease model rats

The purpose of this study was to identify consistent characteristic changes of neuronal activity in basal ganglia (BG) nuclei associated with Parkinson's disease (PD) so that a reliable index of PD can be derived. A simple algorithm for automatic identification of firing patterns was devised as an essential tool to achieve this goal. A detailed quantitative analysis of firing patterns as well as firing rate was performed in three BG nuclei: the subthalamic nucleus (STN), the substantia nigra pars reticulate (SNpr), and the globus pallidus (GP). The results showed that the firing rate of STN neurons was not significantly altered in PD model rats. We also did not find a significant alteration in firing rates in the SNpr and GP between normal and PD model rats. In contrast, consistent changes of firing patterns were observed in all three BG nuclei in that the percentage of neurons with a regular firing pattern decreased whereas those with irregular, mixed, or burst patterns increased. This enables a simple algorithm based on burst detection and the shape of the interspike interval histogram to identify whether the neuronal activity is from normal or PD model rats.

In situ hybridization and immunofluorescence on resin‐embedded tissue to identify the components of Nissl substance

It is not clear whether the Nissl substance is present at the axon hillock. To clarify this gap in knowledge, we conducted in situ hybridization (ISH) on mouse brain tissue using 30-microm cryostat and 1-3-microm acrylic resin sections. Cryostat and rehydrated resin sections were exposed to digoxygenin-labeled glutamic acid decarboxylase 1 sense and antisense riboprobes. Consecutive sections from tissue embedded in resin were subjected to the ribosomal protein L26 primary antibody to determine the distribution of the ribo/polysomes. ISH results from the antisense riboprobe in both cryostat and resin-embedded tissue sections demonstrated an abundance of message in the neurons from the substantia nigra pars reticulate. In addition, the resin sections demonstrated hybridization signal in the axon hillock of some neurons. Immunofluorescence labeling of consecutive sections using an antibody to the most abundant ribosomal protein L26 confirmed their distribution in the cell body and the axon hillock of similar neurons. Compared with the 30-microm cryostat sections, the most striking feature of ISH in the thinner resin (2-3 microm) sections was that there was a phenomenal improvement in the overall clarity and spatial resolution. Reexamination of the axon hillock when continuous with the cell body in cryostat sections revealed that the same message was also present, except it was overlooked initially because of overlapping cell populations in thick tissue slices. As ribosomes are a component of Nissl substance, we propose that the axon hillock, like other parts of the neuron, does contain Nissl substance.

Unilateral 6-hydroxydopamine lesion of dopamine neurons and subchronic l-DOPA administration in the adult rat alters the expression of the vesicular GABA transporter in different subsets of striatal neurons and in the substantia nigra, pars reticulata

The loss of dopamine neurons combined or not with the subsequent administration of l-DOPA in patients with Parkinson’s disease or in experimental models of the disease results in altered GABAergic signaling throughout the basal ganglia, including the striatum and the substantia nigra, pars reticulata. However, the molecular mechanisms involved in altered GABA neurotransmission remain poorly understood. In order to be released from synaptic vesicles, newly synthesized GABA is transported from the cytosol into synaptic vesicles by a vesicular GABA transporter. The objective of this study was to examine the hypothesis that expression of the vesicular GABA transporter (vGAT) is altered in the unilateral 6-hydroxydopamine model of Parkinson’s disease. Our results provide evidence that a unilateral 6-hydroxydopamine lesion results in increased and decreased vGAT mRNA levels in striatopallidal and striatonigral neurons, respectively. These two subsets of neurons were identified by the co-expression or lack of co-expression of preproenkephalin, a marker of striatopallidal neurons, using double-labeling in situ hybridization histochemistry. Such changes occurred in the striatum ipsilateral to the 6-hydroxydopamine lesion and were paralleled by decreased vGAT protein levels in the substantia nigra, pars reticulate (SNr). On the other hand, the subchronic systemic administration of l-DOPA increased vGAT mRNA levels in preproenkephalin-negative neurons on the side ipsilateral and, to a lesser extent, the side contralateral to the 6-hydroxydopamine lesion. Systemic l-DOPA also increased vGAT protein levels in the ipsi- and contralateral SNr. As a whole, the results provide original evidence that vGAT expression is altered in the 6-hydroxydopamine model of Parkinson’s disease. They also suggest that the behavioral effects induced by a subchronic administration of l-DOPA to 6-hydroxydopamine-lesioned rats involve an increase in the vesicular release of GABA by striatonigral neurons.

Dopamine-D 2 and NMDA glutamate receptors regulate striatal gabaergic transmission differently

The loss of dopamine neurons combined or not with the subsequent administration of l-DOPA in patients with Parkinson’s disease or in experimental models of the disease results in altered GABAergic signaling throughout the basal ganglia, including the striatum and the substantia nigra, pars reticulata. However, the molecular mechanisms involved in altered GABA neurotransmission remain poorly understood. In order to be released from synaptic vesicles, newly synthesized GABA is transported from the cytosol into synaptic vesicles by a vesicular GABA transporter. The objective of this study was to examine the hypothesis that expression of the vesicular GABA transporter (vGAT) is altered in the unilateral 6-hydroxydopamine model of Parkinson’s disease. Our results provide evidence that a unilateral 6-hydroxydopamine lesion results in increased and decreased vGAT mRNA levels in striatopallidal and striatonigral neurons, respectively. These two subsets of neurons were identified by the co-expression or lack of co-expression of preproenkephalin, a marker of striatopallidal neurons, using double-labeling in situ hybridization histochemistry. Such changes occurred in the striatum ipsilateral to the 6-hydroxydopamine lesion and were paralleled by decreased vGAT protein levels in the substantia nigra, pars reticulate (SNr). On the other hand, the subchronic systemic administration of l-DOPA increased vGAT mRNA levels in preproenkephalin-negative neurons on the side ipsilateral and, to a lesser extent, the side contralateral to the 6-hydroxydopamine lesion. Systemic l-DOPA also increased vGAT protein levels in the ipsi- and contralateral SNr. As a whole, the results provide original evidence that vGAT expression is altered in the 6-hydroxydopamine model of Parkinson’s disease. They also suggest that the behavioral effects induced by a subchronic administration of l-DOPA to 6-hydroxydopamine-lesioned rats involve an increase in the vesicular release of GABA by striatonigral neurons.

Expression of phosphotyrosine and SNAP-25 immunoreactivity in grumose (foamy) spheroid bodies suggests axonal regeneration.

To investigate the origin of grumose (foamy) spheroid bodies (GFSB), the expression of two proteins associated with axonal regeneration, i.e., phosphotyrosine and 25-kDa synaptosomal-associated protein (SNAP-25), was immunohistochemically assessed in GFSB in the substantia nigra pars reticulate (SNPR) of progressive supranuclear palsy (PSP). Phosphotyrosine immunoreactive (-IR) and SNAP-25-IR were found in many GFSB. Both were expressed intensely on eosinophilic debris and grumose aggregates in GFSB. Our result suggests that GFSB are structures associated with aberrant sprouting of axons in the degenerated SNPR from other regions such as the globus pallidus to the SNPR, and that the aberrant sprouting may be associated with cell signaling involving tyrosine kinase systems.

Necrosis of the Substantia Nigra, Pars Reticulate, in Flurothyl-Induced Status Epilepticus is Ameliorated by the Spin Trap α Phenyl-N- tert-butyl Nitrone

The objective of the present study was to explore whether a diffusible free radical scavenger can ameliorate the pan-neurotic lesions of the substantia nigra, pars reticulate (SNPR), which are incurred in rats subjected to status epilepticus of more than 30 min duration. Vehicle-injected animals had flurothyl seizures induced for 45 min. The seizures were then terminated and the animals were recovered for 7 d to allow histopathological evaluation of the SNPR lesions. Drug-treated animals, which were otherwise treated identically, were given either 100–800 mg/kg of dimethylthiourea (DMTU), a diffusible hydroxyl ion scavenger, or the diffusible spin trap α-phenyl N- tert-butyl nitrone (PBN) in a dose of 100 mg/kg IP. All animals given DMTU died 2 to 8 h after status epilepticus, but PBN was tolerated well by the animals. The amount of flurothyl required to sustain the electrographic seizures was identical in the vehicle- and drug-injected groups, demonstrating that PBN did not suppress seizure activity. Vehicle-injected animals had large bilateral infarcts localized to the SNPR. Of the six animals treated with PBN, one had a small, unilateral lesions, and in all other animals the SNPR had a normal histological appearance. The results strongly suggest that the pan-necrotic lesions of the SNPR incurred during ongoing seizure activity represent a free radical-mediated lesion. Copyright © 1997 Elsevier Science Inc.

ケタミン麻酔ネコ発声に対する黒質網様部の機能的役割の解析

ケタミン麻酔ネコ発声に対する黒質網様部の機能的役割の解析

The substantia nigra pars reticulata, seizures and Fos expression.

The induction of the proto-oncogene c-fos has been used extensively to identify spatially distributed neural systems activated by seizures. The substantia nigra pars reticulata (SNpr) has been implicated as a critical structure in neural networks involved in the modulation of seizure expression, yet the SNpr has not been reported to express Fos following seizures induced in a variety of seizure paradigms. In this study we determined whether (1) the temporal characteristics of Fos induction in the SNpr were different than those of other brain areas following kindled seizures, (2) neurons in the SNpr possess the cellular machinery to express Fos, (3) Fos can be induced in SNpr by direct electrical stimulation, and (4) Fos expression is induced in the SNpr following kainate or pilocarpine-induced status epilepticus. Results indicate that Fos is not induced in SNpr at any time point (1-12 h) after kindled seizures, and that serum response factor, a constitutively expressed nuclear protein necessary for Fos expression, is present in SNpr neurons. Results further indicate that Fos expression in the SNpr is induced following either direct electrical stimulation or pilocarpine status, but not status elicited by kainate. We conclude that, in so far as the SNpr represents a critical structure for modulating seizure expression, seizure activity does not represent a sufficient stimulus to induce Fos in SNpr neurons. Further, the neural networks defined by Fos expression following seizure may be incomplete, and should be interpreted conservatively.