Compulsive use of dopaminergic drug therapy in Parkinson's disease: Reward and anti‐reward

A few Parkinson patients develop a disabling pattern of compulsive dopaminergic drug use (“dopamine dysregulation syndrome”—DDS). DDS patients commonly identify aversive dysphoric “OFF” mood‐states as a primary motivation to compulsively use their drugs. We compared motoric, affective, non‐motor symptoms and incentive arousal after overnight medication withdrawal and after levodopa in DDS and control PD patients. Twenty DDS patients were matched to 20 control PD patients for age, gender, and disease duration and underwent a standard levodopa challenge. Somatic symptomatology, positive and negative affective states, drug effects, reward responsivity, motor disability, and dyskinesias were tested in the “OFF”‐state after overnight withdrawal of medications, and then after a challenge with a standard dose of levodopa, after a full “ON”‐state was achieved. In the “OFF”‐state, DDS patients reported lower positive affect, and more motor and non‐motor disability. In the “ON”‐state, DDS patients had higher expressions of drug “wanting,” reward responsivity, and dyskinesias. Positive and negative affect, non‐motor symptomatology, and motor disability were comparable. These findings suggest that affective, motivational, and motoric disturbances in PD are associated with the transition to compulsive drug use in individuals who inappropriately overuse their dopaminergic medication. © 2010 Movement Disorder Society     

Longitudinal changes in functional connectivity of cortico‐basal ganglia networks in manifests and premanifest huntington's disease

Huntington's disease (HD) is a genetic neurological disorder resulting in cognitive and motor impairments. We evaluated the longitudinal changes of functional connectivity in sensorimotor, associative and limbic cortico‐basal ganglia networks. We acquired structural MRI and resting‐state fMRI in three visits one year apart, in 18 adult HD patients, 24 asymptomatic mutation carriers (preHD) and 18 gender‐ and age‐matched healthy volunteers from the TRACK‐HD study. We inferred topological changes in functional connectivity between 182 regions within cortico‐basal ganglia networks using graph theory measures. We found significant differences for global graph theory measures in HD but not in preHD. The average shortest path length (L) decreased, which indicated a change toward the random network topology. HD patients also demonstrated increases in degree k, reduced betweeness centrality bc and reduced clustering C. Changes predominated in the sensorimotor network for bc and C and were observed in all circuits for k. Hubs were reduced in preHD and no longer detectable in HD in the sensorimotor and associative networks. Changes in graph theory metrics (L, k, C and bc) correlated with four clinical and cognitive measures (symbol digit modalities test, Stroop, Burden and UHDRS). There were no changes in graph theory metrics across sessions, which suggests that these measures are not reliable biomarkers of longitudinal changes in HD. preHD is characterized by progressive decreasing hub organization, and these changes aggravate in HD patients with changes in local metrics. HD is characterized by progressive changes in global network interconnectivity, whose network topology becomes more random over time. Hum Brain Mapp 37:4112–4128, 2016. © 2016 Wiley Periodicals, Inc.     

Power‐law temporal autocorrelation of activity reflects severity of parkinsonism

We aimed to obtain a reliable, objective scale representing disease severity for appropriate management of patients with Parkinson's disease (PD). Nineteen patients with PD at the Department of Neurology, Tokyo University Hospital, were classified into mild (n = 10) or severe groups (n = 9) depending on their Hoehn‐Yahr scores, and wore accelerometers on their wrists for more than 6 consecutive days. During this time we monitored their subjective assessments of symptom severity and analyzed the power‐law exponents (α) for local maxima and minima of fluctuations in the activity time series. Statistical comparisons were made between the severe and mild groups and of individual patients on “good condition” and “bad condition” days, as well as between days before and after antiparkinsonism medication. In all patients, the α for local maxima was always lower when parkinsonism was mild than when severe. Presence of tremor did not influence the α for local maxima. As the lower α value for local maxima of fluctuations in activity records reflects more frequent switching behavior from low to high physical activities or the severity of akinesia, actigraph monitoring of parkinsonism, and analysis of its power‐law correlation may provide useful objective information for controlling parkinsonism in outpatient clinics and for evaluating new antiparkinsonism drugs. © 2007 Movement Disorder Society     

Dysregulated expression of secretogranin III is involved in neurotoxin‐induced dopaminergic neuron apoptosis

The neurotoxins paraquat (PQ) and dopamine (DA or 6‐OHDA) cause apoptosis of dopaminergic neurons in the substantia nigra pars compacta (SNpc), reproducing an important pathological feature of Parkinson's disease (PD). Secretogranin III (SCG3), a member of the multifunctional granin family, plays a key role in neurotransmitter storage and transport and in secretory granule biogenesis, which involves the uptake of exogenous toxins and endogenous “toxins” in neuroendocrine cells. However, the molecular mechanisms of neurotoxin‐induced apoptosis in dopaminergic neurons and the role of SCG3‐associated signaling pathways in neuroendocrine regulation are unclear. To address this, we used PQ‐ and DA‐induced apoptosis in SH‐SY5Y human dopaminergic cells as an in vitro model to investigate the association between SCG3 expression level and apoptosis. SCG3 was highly expressed in SH‐SY5Y cells, and SCG3 mRNA and protein levels were dramatically decreased after PQ treatment. Apoptosis induced by PQ is associated with caspase activation and decreased SCG3 expression, and restoration of SCG3 expression is observed after treatment with caspase inhibitors. Overexpressed SCG3 in nonneuronal cells and endogenous SCG3 in SH‐SY5Y cells are cleaved into specific fragments by recombinant caspase‐3 and ‐7, but the fragments were not detected in PQ‐treated SH‐SY5Y cells. Therefore, SCG3 may be involved in apoptosis signal transduction as a caspase substrate, leading to loss of its original biological functions. In addition, SCG3 may be a pivotal component of the neuroendocrine pathway and play an important role in neuronal communication and neurotransmitter release, possibly representing a new potential target in the course of PD pathogenesis. © 2012 Wiley Periodicals, Inc.     

Poly(ADP‐ribose)polymerase inhibitor can attenuate the neuronal death after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurotoxicity in mice

An excessive expression of poly(ADP‐ribose)polymerase (PARP) has been demonstrated to play a key role in the pathogenesis of Parkinson's disease (PD). Here we investigated the therapeutic effect of the PARP inhibitor benzamide against 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) neurotoxicity in mice. In our HPLC and Western blot analysis, pretreatment with benzamide showed a neuroprotective effect against MPTP neurotoxicity in mice. Posttreatment with benzamide also attenuated MPTP neurotoxicity in mice. Furthermore, our immunohistochemical study showed that posttreatment with benzamide significantly prevented neuronal damage by suppressing overexpression of neuronal, microglial, and astroglial PARP after MPTP treatment. These findings have important implications for the therapeutic time window and choice of PARP inhibitors in PD patients. Our present findings provide further evidence that PARP inhibitor may offer a novel therapeutic strategy for PD. © 2009 Wiley‐Liss, Inc.     

Long‐term effect of unilateral pallidotomy on levodopa‐induced dyskinesia

Unilateral pallidotomy has been effectively used to treat parkinsonism and reduce levodopa induced dyskinesia (LID). We sought to determine the long‐term effects of pallidotomy on LID in 10 patients who had initial benefit from pallidotomy but went on to require DBS surgery for symptom progression. The Dyskinesia Rating Scale (DRS) was used to rate and quantify LID in a blinded fashion. Though sample size was small, there was a trend towards a reduction in LID lasting up to 12 years suggesting that posteroventral pallidotomy may provide sustained benefit in reducing LID. © 2010 Movement Disorder Society     

High‐frequency stimulation of the subthalamic nucleus modulates neuronal activity in the lateral habenula nucleus

High‐frequency stimulation (HFS) of the subthalamic nucleus (STN) is often used to treat movement disability in advanced Parkinson's disease, but some patients experience debilitating psychiatric effects including depression. Interestingly, HFS of the STN modulates 5‐HT neurons in the dorsal raphe nucleus (DRN) which are linked to depression, but the neural substrate of this effect is unknown. Here, we tested the effect of STN stimulation on neuronal activity in the lateral habenula nucleus (LHb), an important source of input to DRN 5‐HT neurons and also a key controller of emotive behaviours. LHb neurons were monitored in anaesthetized rats using single‐unit extracellular recording, and localization within the LHb was confirmed by juxtacellular labelling. HFS of the STN (130 Hz) evoked rapid changes in the firing rate of the majority of LHb neurons tested (38 of 68). Some LHb neurons (19/68) were activated by HFS, while others (19/68), distinguished by a higher basal firing rate, were inhibited. LHb neurons that project to the DRN were identified using antidromic activation and collision testing (n = 17 neurons). Some of these neurons (5/17) were also excited by HFS of the STN, and others (7/17) were inhibited although this was only a statistical trend. In summary, HFS of the STN modulated the firing of LHb neurons, including those projecting to the DRN. The data identify that the STN impacts on the LHb‐DRN pathway. Moreover, this pathway may be part of the circuitry mediating the psychiatric effects of STN stimulation experienced by patients with Parkinson's disease.     

Cross‐sectional and longitudinal studies of three‐dimensional stereotactic surface projection SPECT analysis in Parkinson's disease

Although dementia is increasingly recognized as a common feature in Parkinson's disease (PD), its pathological substrate remains unknown. We conducted cross‐sectional and longitudinal brain perfusion SPECT analyses to explore changes during the course of developing dementia in PD. Fifty‐five patients originally diagnosed with PD were imaged in the cross‐sectional study. Twenty‐one of these, nine without dementia and 12 with dementia (PDD), were included in the longitudinal study to observe perfusion changes during the course of their disease. Data were analyzed using three‐dimensional stereotactic surface projection SPECT analysis. The UK Parkinson's Disease Society Brain Bank criteria were used to diagnose PD and the revised criteria for the clinical diagnosis of dementia with Lewy bodies for PDD. The cross‐sectional study showed that patients with PDD had significantly reduced perfusion in the right posterior cingulate, the right precuneus and the left posterior cingulate area. In the longitudinal study, significantly reduced perfusion was observed in the left anterior frontal gyrus in PD without dementia, and in the right inferior parietal lobule in those that developed PDD. We suggest that a relationship exists between developing dementia in PDD and reduced perfusion in the posterior parietal area. © 2009 Movement Disorder Society     

Downregulation of miR‐7116‐5p in microglia by MPP+ sensitizes TNF‐α production to induce dopaminergic neuron damage

Activation of microglia resulting in exacerbated inflammation expression plays an important role in degeneration of dopaminergic (DA) neurons in the pathogenesis of Parkinson's disease (PD). However, how this enhanced inflammation is induced in microglia remains largely unclear. Here, in the mouse PD model induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetra hydropyridine (MPTP), we found that miR‐7116‐5p in microglia has a crucial role in this inflammation. 1‐methyl‐4‐phenylpyridinium (MPP⁺) is uptaken by microglia through organic cation transporter 3 (OCT3) to downregulate miR‐7116‐5p, an miRNA found to target tumor necrosis factor alpha (TNF‐α). Production of TNF‐α in microglia is specifically potentiated by MPP⁺ via downregulation of miR‐7116‐5p to elicit subsequent inflammatory responses. Furthermore, enhancement of miR‐7116‐5p expression in microglia in mice inhibits the production of TNF‐α and the activation of glia, and further prevents loss of DA neurons. Together, our studies suggest that MPP⁺ suppresses miR‐7116‐5p level in microglia and potentiates TNF‐α production and inflammatory responses to contribute to DA neuron damage.     

Deficits in motor performance after pedunculopontine lesions in rats – impairment depends on demands of task

Anatomically and functionally located between basal ganglia and brainstem circuitry, the pedunculopontine tegmental nucleus (PPTg) is in a pivotal position to contribute to motor behavior. Studies in primates have reported akinesia and postural instability following destruction of the PPTg. In humans, the PPTg partially degenerates in Parkinson's disease and stimulation of this region is under investigation as a possible therapeutic. Studies in rats report no crude motor impairment following PPTg lesion, although a detailed assessment of the role of the PPTg in rat motor function has not been reported. Our studies applied motor tests generally used in rodent models of Parkinson's disease to rats bearing either excitotoxic damage to all neuronal populations within PPTg, or selective destruction of the cholinergic subpopulation created with the toxin Dtx‐UII. Neither lesion type altered baseline locomotion. On the rotarod, excitotoxic lesions produced a persistent impairment on the accelerating, but not fixed speed, conditions. In the vermicelli handling task (a quantitative measure of fine motor control and effective behavioral sequencing) excitotoxic lesions produced no single impairment, but globally increased the number of normal and abnormal behaviors. In contrast, depletion of cholinergic PPTg neurons produced impairment on the accelerating rotarod but no changes in vermicelli handling. Together, these results show that while PPTg lesions produce no impairment in the execution of individual motor actions, impairments emerge when the demands of the task increase. Results are discussed in terms of PPTg acting as part of a rapid action selection system, which integrates sensory information into motor output.