Functional Topography of the Human Subthalamic Nucleus: Relevance for Subthalamotomy in Parkinson's Disease.

BACKGROUND: The subthalamic nucleus (STN) is considered a key structure in motor, behavioral, and emotional control. Although identification of the functional topography of the STN has therapeutic implications in the treatment of the motor features of Parkinson's disease (PD), the details of its functional and somatotopic organization in humans are not well understood. OBJECTIVE: The aim of this study was to characterize the functional organization of the STN and its correlation with the motor outcomes induced by subthalamotomy. METHODS: We used diffusion-weighted imaging to assess STN connectivity patterns in 23 healthy control subjects and 86 patients with PD, of whom 39 received unilateral subthalamotomy. Analytical tractography was used to reconstruct structural cortico-subthalamic connectivity. A diffusion-weighted imaging/functional magnetic resonance imaging-driven somatotopic parcellation of the STN was defined to delineate the representation of the upper and lower limb in the STN. RESULTS: We confirmed a connectional gradient to sensorimotor, supplementary-motor, associative, and limbic cortical regions, spanning from posterior-dorsal-lateral to anterior-ventral-medial portions of the STN, with intermediate overlapping zones. Functional magnetic resonance imaging-driven parcellation demonstrated dual segregation of motor cortico-subthalamic projections in humans. Moreover, the relationship between lesion topography and functional anatomy of the STN explains specific improvement in bradykinesia, rigidity, and tremor induced by subthalamotomy. CONCLUSIONS: Our results support an interplay between segregation and integration of cortico-subthalamic projections, suggesting the coexistence of parallel and convergent information processing. Identifying the functional topography of the STN will facilitate better definition of the optimal location for functional neurosurgical approaches, that is, electrode placement and lesion location, and improve specific cardinal features in PD. © 2021 International Parkinson and Movement Disorder Society.

Consensus Paper: Experimental Neurostimulation of the Cerebellum.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease.

Circuitry models of Parkinson's disease (PD) are based on striatal dopamine loss and aberrant striatal inputs into the basal ganglia network. However, extrastriatal mechanisms have increasingly been the focus of attention, whereas the status of striatal discharges in the parkinsonian human brain remains conjectural. We now report the activity pattern of striatal projection neurons (SPNs) in patients with PD undergoing deep brain stimulation surgery, compared with patients with essential tremor (ET) and isolated dystonia (ID). The SPN activity in ET was very low (2.1 ± 0.1 Hz) and reminiscent of that found in normal animals. In contrast, SPNs in PD fired at much higher frequency (30.2 ± 1.2 Hz) and with abundant spike bursts. The difference between PD and ET was reproduced between 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and normal nonhuman primates. The SPN activity was also increased in ID, but to a lower level compared with the hyperactivity observed in PD. These results provide direct evidence that the striatum contributes significantly altered signals to the network in patients with PD.

Basal ganglia, movement disorders and deep brain stimulation: advances made through non-human primate research.

Studies in non-human primates (NHPs) have led to major advances in our understanding of the function of the basal ganglia and of the pathophysiologic mechanisms of hypokinetic movement disorders such as Parkinson's disease and hyperkinetic disorders such as chorea and dystonia. Since the brains of NHPs are anatomically very close to those of humans, disease states and the effects of medical and surgical approaches, such as deep brain stimulation (DBS), can be more faithfully modeled in NHPs than in other species. According to the current model of the basal ganglia circuitry, which was strongly influenced by studies in NHPs, the basal ganglia are viewed as components of segregated networks that emanate from specific cortical areas, traverse the basal ganglia, and ventral thalamus, and return to the frontal cortex. Based on the presumed functional domains of the different cortical areas involved, these networks are designated as 'motor', 'oculomotor', 'associative' and 'limbic' circuits. The functions of these networks are strongly modulated by the release of dopamine in the striatum. Striatal dopamine release alters the activity of striatal projection neurons which, in turn, influences the (inhibitory) basal ganglia output. In parkinsonism, the loss of striatal dopamine results in the emergence of oscillatory burst patterns of firing of basal ganglia output neurons, increased synchrony of the discharge of neighboring basal ganglia neurons, and an overall increase in basal ganglia output. The relevance of these findings is supported by the demonstration, in NHP models of parkinsonism, of the antiparkinsonian effects of inactivation of the motor circuit at the level of the subthalamic nucleus, one of the major components of the basal ganglia. This finding also contributed strongly to the revival of the use of surgical interventions to treat patients with Parkinson's disease. While ablative procedures were first used for this purpose, they have now been largely replaced by DBS of the subthalamic nucleus or internal pallidal segment. These procedures are not only effective in the treatment of parkinsonism, but also in the treatment of hyperkinetic conditions (such as chorea or dystonia) which result from pathophysiologic changes different from those underlying Parkinson's disease. Thus, these interventions probably do not counteract specific aspects of the pathophysiology of movement disorders, but non-specifically remove the influence of the different types of disruptive basal ganglia output from the relatively intact portions of the motor circuitry downstream from the basal ganglia. Knowledge gained from studies in NHPs remains critical for our understanding of the pathophysiology of movement disorders, of the effects of DBS on brain network activity, and the development of better treatments for patients with movement disorders and other neurologic or psychiatric conditions.

Primary motor cortex of the parkinsonian monkey: altered encoding of active movement.

Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson's disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically-identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement-related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement-related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (-22%), speed (-40%), acceleration (-49%) and hand position (-33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (-50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes beginning in the 150-ms period that immediately preceded movement. Overall, the results are consistent with proposals that under-activation and abnormal timing of movement-related activity in M1 contribute to parkinsonian motor signs but are not consistent with the idea that a loss of functional specificity plays an important role. Given that pyramidal tract-type neurons form the primary efferent pathway that conveys motor commands to the spinal cord, the dysfunction of movement-related activity in pyramidal tract-type neurons is likely to be a central factor in the pathophysiology of parkinsonian motor signs.

Deep brain stimulation of the centromedian thalamic nucleus for essential tremor: a case report.

The centromedian nucleus (CM) of the thalamus is an important site with anatomical connections to different cortical and subcortical motor areas; however, its role in tremor disorders is not clear, although deep brain stimulation (DBS) of the CM has been described to be effective in the treatment of parkinsonian tremor. We report a case of a patient with medication-refractory essential tremor (ET) who had excellent tremor suppression with DBS of the CM. The CM and the nearby region should be explored as a potential target for the treatment of ET and other forms of tremor.

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease.

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action.

Proceedings of the Second Annual Deep Brain Stimulation Think Tank: What's in the Pipeline.

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

The focal dystonias: current views and challenges for future research.

The most common forms of dystonia are those that develop in adults and affect a relatively isolated region of the body. Although these adult-onset focal dystonias are most prevalent, knowledge of their etiologies and pathogenesis has lagged behind some of the rarer generalized dystonias, in which the identification of genetic defects has facilitated both basic and clinical research. This summary provides a brief review of the clinical manifestations of the adult-onset focal dystonias, focusing attention on less well understood clinical manifestations that need further study. It also provides a simple conceptual model for the similarities and differences among the different adult-onset focal dystonias as a rationale for lumping them together as a class of disorders while at the same time splitting them into subtypes. The concluding section outlines some of the most important research questions for the future. Answers to these questions are critical for advancing our understanding of this group of disorders and for developing novel therapeutics.

Phenomenology and classification of dystonia: a consensus update.

This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. © 2013 Movement Disorder Society.

Patients with Cognitive Impairment in Parkinson's Disease Benefit from Deep Brain Stimulation: A Case-Control Study.

Background: Deep brain stimulation (DBS) for Parkinson's disease (PD) is generally contraindicated in persons with dementia but it is frequently performed in people with mild cognitive impairment or normal cognition, and current clinical guidelines are primarily based on these cohorts. Objectives: To determine if moderately cognitive impaired individuals including those with mild dementia could meaningfully benefit from DBS in terms of motor and non-motor outcomes. Methods: In this retrospective case-control study, we identified a cohort of 40 patients with PD who exhibited moderate (two or more standard deviations below normative scores) cognitive impairment (CI) during presurgical workup and compared their 1-year clinical outcomes to a cohort of 40 matched patients with normal cognition (NC). The surgery targeted subthalamus, pallidus or motor thalamus, in a unilateral, bilateral or staged approach. Results: At preoperative baseline, the CI cohort had higher Unified Parkinson's Disease Rating Scale (UPDRS) subscores, but similar levodopa responsiveness compared to the NC cohort. The NC and CI cohorts demonstrated comparable degrees of postoperative improvement in the OFF-medication motor scores, motor fluctuations, and medication reduction. There was no difference in adverse event rates between the two cohorts. Outcomes in the CI cohort did not depend on the target, surgical staging, or impaired cognitive domain. Conclusions: Moderately cognitively impaired patients with PD can experience meaningful motor benefit and medication reduction with DBS.

Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation.

Frontal circuits play a critical role in motor, cognitive, and affective processing - and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)function remains largely elusive. Here, we study 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregate the frontal cortex into circuits that became dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to rostral, ranging from interconnections with sensorimotor cortices in dystonia, with the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairment in the human brain.

Milestones in research on the pathophysiology of Parkinson's disease.

Progress in our understanding of the mechanisms underlying the cardinal motor abnormalities of Parkinson's disease (PD), in particular akinesia and bradykinesia and their treatment, has been remarkable. Notable accomplishments include insights into the functional organization of the basal ganglia and their place in the motor system as components of a family of parallel cortico-subcortical circuits that subserve motor and nonmotor functions and the development of models of the intrinsic organization of the basal ganglia, including delineation of the so-called direct, indirect, and hyperdirect pathways. Studies in primate models of PD have provided insight into the alterations of neuronal activity that are responsible for the motor features of PD, revealing both altered tonic levels of discharge and significant disturbances of the patterns of discharge throughout the motor circuitry and have led to the formulation of circuit models of PD, providing testable hypotheses for research and stimulating the development of new therapies. Most importantly, the discovery that lesions of the subthalamic nucleus, a key node of the indirect pathway, abolish the cardinal features of PD contributed to the renaissance in the use of surgical approaches to treating patients with PD, including ablation and deep brain stimulation.

Intraoperative neurophysiology in DBS for dystonia.

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) has been demonstrated to be an effective therapy for the treatment of primary dystonia as well as tardive dystonia. Results for other forms of secondary dystonia have been less consistent. Although a number of target sites have been explored for the treatment of dystonia, most notably the motor thalamus, the target of choice remains the sensorimotor portion of the GPi. Although the optimal site within the GPi has not been determined, most centers agree that the optimal site involves the posteroventral lateral "sensorimotor" portion of the GPi. Microelectrode recording (MER) can be used to identify boundaries of the GPi and nearby white matter tracts, including the corticospinal tract and optic tract, and the sensorimotor GPi. However, whether or not the use of MER leads to improved outcomes compared with procedures performed without MER has not been determined. Currently, there is no evidence to support or refute the hypothesis that mapping structures with MER provides better short- or long-term outcomes. Centers using MER do not report a preference of one system over another, but there have not been any studies to compare the relative benefits or risks of using more than 1 electrode simultaneously. Comparison studies of different target structures and targeting techniques in dystonia have not been performed. Additional research, which includes comparative studies, is needed to advance our understanding and optimization of DBS targets, techniques, and approaches along with their relative benefits and risks in dystonia.