Subthalamic Neuronal Firing in Obsessive-Compulsive Disorder and Parkinson Disease

Grenoble University, France.
Annals of Neurology (Impact Factor: 9.98). 05/2011; 69(5):793-802. DOI: 10.1002/ana.22222
Source: PubMed


Although electrophysiologic dysfunction of the subthalamic nucleus is putative, deep brain stimulation of this structure has recently been reported to improve obsessions and compulsions. In Parkinson disease, sensorimotor subthalamic neurons display high-frequency burst firing, which is considered as an electrophysiologic signature of motor loop dysfunction. We addressed whether such neuronal dysfunction of the subthalamic nucleus also exists in the nonmotor loops involved in patients with obsessive-compulsive disorder.
We compared the neuronal activity of the subthalamic nucleus recorded in 9 patients with obsessive-compulsive disorder with that of 11 patients with Parkinson disease measured during intraoperative exploration for deep brain stimulation.
The mean subthalamic neuron discharge rate was statistically lower in patients with obsessive-compulsive disorder than in patients with Parkinson disease (20.5 ± 11.0 Hz, n = 100 and 30.8 ± 15.6 Hz, n = 93, respectively, p < 0.001). The relative proportion of burst neurons did not differ significantly between the 2 diseases (75% vs 73%). Interestingly, burst neurons were predominantly left-sided in obsessive-compulsive disorder.
The recording of burst neurons within the nonmotor subthalamic nucleus in patients with obsessive-compulsive disorder is a novel finding that suggests the existence of deregulation of the nonmotor basal ganglia loop, possibly left-sided. Potentially, burst activity might interfere with normal processes occurring within nonmotor loops.

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Available from: Stephan Chabardes, Jul 02, 2014
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    • "These data confirmed that deep brain stimulation applied to this target reduced obsessive–compulsive disorder symptoms (Mallet et al., 2008). Although the reason for this improvement remained unclear, recent electrophysiological data suggest a dysfunctioning of the STN in obsessive–compulsive disorder (Piallat et al., 2011; Welter et al., 2011). Because surgery in these patients makes it possible to record neuronal activity perioperatively in the therapeutic target, we took advantage of this opportunity to test two hypotheses: (i) individual neurons located in the associative-limbic region of the STN might be influenced by cognitive and emotional information; and (ii) doubt revealed by checking behaviour might modify their activity. "
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    ABSTRACT: Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.
    Full-text · Article · Jan 2013 · Brain
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    • "Firing rate was lower in OCD and closer to that of animal controls, and would thus be more " normal " than in PD. On the other hand, burst activity was increased in the anterior ventromedial area, in line with a previous study (Piallat et al., 2011) and the associative and limbic functions associated to that area (Karachi et al., 2005). Furthermore , a number of burst parameters and oscillatory activities (delta and alpha bands) were correlated to symptom severity; some of these characteristics were predictive of response to treatment by DBS (Welter et al., 2011). "
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    ABSTRACT: Since the early 90s, the subthalamic nucleus (STN) has started to be the subject of an increasing interest not only in the community of the basal ganglia scientists but also for neurosurgeons and neurologists, thanks to the development of the surgical treatment for Parkinson's disease. The involvement of the STN in cognitive and motivational processes has been demonstrated since, and psychiatrists are now considering this small structure as a possible target for the treatment of various disorders. In this review, we will address six questions to highlight (1) How increased knowledge has led us from a strictly motor model to an integrative one. (2) How knowledge acquired in animal models can be similar or (3) different from the effects observed in human patients. (4) How clinical trials are sometimes ahead of fundamental research carried out in animals, showing effects that could not be predicted on the basis of animal studies, thus questioning the relevance of some animal models, especially for psychiatric disorders. We will also address the possible future orientations (5) and how the use, or precaution not to use, certain key words in animal research dedicated to STN functions can lead to the omission of a certain amount of available data in the literature (6).
    Full-text · Article · Dec 2011 · Neuroscience
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    • "However, this hypothesis awaits confirmation of intracellular calcium increase in response to mGluR5 activation on nigral dopaminergic neurons. In addition to these postsynaptic effects, mGluR5 blockers may also reduce the activity of glutamatergic inputs to the substantia nigra pars compacta, specifically those from subthalamic nucleus neurons, which strongly respond to mGluR5 activation and display abnormal increased activity in parkinsonism (Rodriguez et al., 1998; Bezard et al., 1999; Awad et al., 2000; Breysse et al., 2003; Fazal et al., 2003; Shimo and Wichmann 2009; Piallat et al., 2011). Another mechanism by which MTEP protection could be mediated is through the regulation of the potentiating effects of mGluR5 upon N-methyl-D-aspartic acid receptor function (Calabresi et al., 1998; Tu et al., 1999; Awad et al., 2000; Alagarsamy et al., 2002). "
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    ABSTRACT: Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease.
    Full-text · Article · Jul 2011 · Brain
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