The subthalamic nucleus : Part I: Development, cytology, topography and connections

This monograph on the subthalamic nucleus accentuates in Part I the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections. The light and electron microscopical cytology concerns the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses: enzymes, NO, GRAP, calcium binding proteins, and receptors (dopamine, cannabinoid, piod, glutamate, GABA, serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historial point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections

Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease

Background: Although the short-term benefits of bilateral stimulation of the subthalamic nucleus in patients with advanced Parkinson's disease have been well documented, the long-term outcomes of the procedure are unknown. Methods: We conducted a five-year prospective study of the first 49 consecutive patients whom we treated with bilateral stimulation of the subthalamic nucleus. Patients were assessed at one, three, and five years with levodopa (on medication) and without levodopa (off medication), with use of the Unified Parkinson's Disease Rating Scale. Seven patients did not complete the study: three died, and four were lost to follow-up. Results: As compared with base line, the patients' scores at five years for motor function while off medication improved by 54 percent (P<0.001) and those for activities of daily living improved by 49 percent (P<0.001). Speech was the only motor function for which off-medication scores did not improve. The scores for motor function on medication did not improve one year after surgery, except for the dyskinesia scores. On-medication akinesia, speech, postural stability, and freezing of gait worsened between year 1 and year 5 (P<0.001 for all comparisons). At five years, the dose of dopaminergic treatment and the duration and severity of levodopa-induced dyskinesia were reduced, as compared with base line (P<0.001 for each comparison). The average scores for cognitive performance remained unchanged, but dementia developed in three patients after three years. Mean depression scores remained unchanged. Severe adverse events included a large intracerebral hemorrhage in one patient. One patient committed suicide. Conclusions: Patients with advanced Parkinson's disease who were treated with bilateral stimulation of the subthalamic nucleus had marked improvements over five years in motor function while off medication and in dyskinesia while on medication. There was no control group, but worsening of akinesia, speech, postural stability, freezing of gait, and cognitive function between the first and the fifth year is consistent with the natural history of Parkinson's disease

Decisional impulsivity and the associative-limbic subthalamic nucleus in obsessive-compulsive disorder: stimulation and connectivity.

Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the anterior and ventral subthalamic nucleus. We further show that evidence accumulation is associated with anterior associative-limbic subthalamic nucleus and right dorsolateral prefrontal functional connectivity in healthy controls, a region implicated in decision-making under uncertainty. Together, our findings highlight specificity of the anterior associative-limbic subthalamic nucleus in decisional impulsivity. Given increasing interest in the potential for subthalamic stimulation in psychiatric disorders and the neuropsychiatric symptoms of Parkinson's disease, these findings have clinical implications for behavioural symptoms and cognitive effects as a function of localization of subthalamic stimulation.This work was supported by Agence Nationale de la Recherche (grant number ANR-14-CE13-0030-01 Physiobs); and University Hospital of Grenoble (Direction de la Recherche Clinique et de l’Innovation). This work was supported by a Wellcome Trust Fellowship grant to V.V. (983705/Z/10/Z)

Imaging the Centromedian Thalamic Nucleus Using Quantitative Susceptibility Mapping.

The centromedian (CM) nucleus is an intralaminar thalamic nucleus that is considered as a potentially effective target of deep brain stimulation (DBS) and ablative surgeries for the treatment of multiple neurological and psychiatric disorders. However, the structure of CM is invisible on the standard T1- and T2-weighted (T1w and T2w) magnetic resonance images, which hamper it as a direct DBS target for clinical applications. The purpose of the current study is to demonstrate the use of quantitative susceptibility mapping (QSM) technique to image the CM within the thalamic region. Twelve patients with Parkinson's disease, dystonia, or schizophrenia were included in this study. A 3D multi-echo gradient recalled echo (GRE) sequence was acquired together with T1w and T2w images on a 3-T MR scanner. The QSM image was reconstructed from the GRE phase data. Direct visual inspection of the CM was made on T1w, T2w, and QSM images. Furthermore, the contrast-to-noise ratios (CNRs) of the CM to the adjacent posterior part of thalamus on T1w, T2w, and QSM images were compared using the one-way analysis of variance (ANOVA) test. QSM dramatically improved the visualization of the CM nucleus. Clear delineation of CM compared to the surroundings was observed on QSM but not on T1w and T2w images. Statistical analysis showed that the CNR on QSM was significantly higher than those on T1w and T2w images. Taken together, our results indicate that QSM is a promising technique for improving the visualization of CM as a direct targeting for DBS surgery

Potential mechanisms for imperfect synchronization in parkinsonian basal ganglia

Neural activity in the brain of parkinsonian patients is characterized by the intermittently synchronized oscillatory dynamics. This imperfect synchronization, observed in the beta frequency band, is believed to be related to the hypokinetic motor symptoms of the disorder. Our study explores potential mechanisms behind this intermittent synchrony. We study the response of a bursting pallidal neuron to different patterns of synaptic input from subthalamic nucleus (STN) neuron. We show how external globus pallidus (GPe) neuron is sensitive to the phase of the input from the STN cell and can exhibit intermittent phase-locking with the input in the beta band. The temporal properties of this intermittent phase-locking show similarities to the intermittent synchronization observed in experiments. We also study the synchronization of GPe cells to synaptic input from the STN cell with dependence on the dopamine-modulated parameters. Dopamine also affects the cellular properties of neurons. We show how the changes in firing patterns of STN neuron due to the lack of dopamine may lead to transition from a lower to a higher coherent state, roughly matching the synchrony levels observed in basal ganglia in normal and parkinsonian states. The intermittent nature of the neural beta band synchrony in Parkinson's disease is achieved in the model due to the interplay of the timing of STN input to pallidum and pallidal neuronal dynamics, resulting in sensitivity of pallidal output to the phase of the arriving STN input. Thus the mechanism considered here (the change in firing pattern of subthalamic neurons through the dopamine-induced change of membrane properties) may be one of the potential mechanisms responsible for the generation of the intermittent synchronization observed in Parkinson's disease.Comment: 27 pages, 9 figure

Optogenetics and deep brain stimulation neurotechnologies

Brain neural network is composed of densely packed, intricately wired neurons whose activity patterns ultimately give rise to every behavior, thought, or emotion that we experience. Over the past decade, a novel neurotechnique, optogenetics that combines light and genetic methods to control or monitor neural activity patterns, has proven to be revolutionary in understanding the functional role of specific neural circuits. We here briefly describe recent advance in optogenetics and compare optogenetics with deep brain stimulation technology that holds the promise for treating many neurological and psychiatric disorders

Informed consent decision-making in deep brain stimulation

Deep brain stimulation (DBS) has proved useful for several movement disorders (Parkinson’s disease, essential tremor, dystonia), in which first and/or second line pharmacological treatments were inefficacious. Initial evidence of DBS efficacy exists for refractory obsessive-compulsive disorder, treatment-resistant major depressive disorder, and impulse control disorders. Ethical concerns have been raised about the use of an invasive surgical approach involving the central nervous system in patients with possible impairment in cognitive functioning and decision-making capacity. Most of the disorders in which DBS has been used might present with alterations in memory, attention, and executive functioning, which may have an impact on the mental capacity to give informed consent to neurosurgery. Depression, anxiety, and compulsivity are also common in DBS candidate disorders, and could also be associated with an impaired capacity to consent to treatment or clinical research. Despite these issues, there is limited empirical knowledge on the decision-making levels of these patients. The possible informed consent issues of DBS will be discussed by focusing on the specific treatable diseases

Existing motor state is favored at the expense of new movement during 13-35 Hz oscillatory synchrony in the human corticospinal system

Oscillations in local field potentials in the β-frequency band (13-35 Hz) are a pervasive feature of human and nonhuman primate motor cortical areas. However, the function of such synchronous activity across populations of neurons remains unknown. Here, we test the hypothesis that β activity may promote existing motor set and posture while compromising processing related to new movements. Three experiments were performed. First, healthy subjects were instructed to make reaction time movements of the outstretched index finger in response to imperative cues triggered by transient increases in corticospinal synchrony, as evidenced by phasic elevations of β-frequency band microtremor and intermuscular synchrony. Second, healthy subjects were instructed to resist a stretch to the index finger triggered in the same way. Finger acceleration in the reaction time task and transcortical components of the stretch reflex were measured and compared with those elicited by random cue or stretch presentation. Finally, we sought a correlation between finger acceleration in the reaction time task and cortical synchrony directly measured from the electrocorticogram in two patients undergoing functional neurosurgery. We demonstrate that movements are slowed and transcortical responses to stretch are potentiated during periods of elevated β-band cortical synchrony. The results suggest that physiological periods of β synchrony are associated with a cortical state in which postural set is reinforced, but the speed of new movements impaired. The findings are of relevance to Parkinson's disease, in which subcortical and cortical β-band synchronization is exaggerated in the setting of increased tone and slowed movements