Deep brain stimulation for movement disorder treatment: exploring frequency-dependent efficacy in a computational network model

A large-scale computational model of the basal ganglia network and thalamus is proposed to describe movement disorders and treatment effects of deep brain stimulation (DBS). The model of this complex network considers three areas of the basal ganglia region: the subthalamic nucleus (STN) as target area of DBS, the globus pallidus, both pars externa and pars interna (GPe-GPi), and the thalamus. Parkinsonian conditions are simulated by assuming reduced dopaminergic input and corresponding pronounced inhibitory or disinhibited projections to GPe and GPi. Macroscopic quantities are derived which correlate closely to thalamic responses and hence motor programme fidelity. It can be demonstrated that depending on different levels of striatal projections to the GPe and GPi, the dynamics of these macroscopic quantities (synchronisation index, mean synaptic activity and response efficacy) switch from normal to Parkinsonian conditions. Simulating DBS of the STN affects the dynamics of the entire network, increasing the thalamic activity to levels close to normal, while differing from both normal and Parkinsonian dynamics. Using the mentioned macroscopic quantities, the model proposes optimal DBS frequency ranges above 130 Hz.

Functional

This chapter discusses pain, movement disorders, epilepsy, dystonia, and neuropsychiatric disorder. The first set of studies examines the efficacy of spinal cord stimulation in managing pain in patients with chronic back pain and extremity pain, chronic pain, and neuropathic pain. The second set of studies evaluates the efficacy of deep brain stimulation of the subthalamic nucleus for the management of severe motor complications of Parkinson’s disease and compares it with ablative options such as unilateral pallidotomy. The third set of studies assesses the therapeutic value of nerve stimulation for patients with refractory epilepsy as well as its impact in seizure reduction. The next study explores the safety and efficacy of bilateral globus pallidus pars interna (GPi) stimulation for cervical dystonia, a complex condition that is often refractory to multiple medical and procedural therapies. Finally, the last study determines whether daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) safely and effectively treats major depressive disorder.

Case studies in neuroscience: deep brain stimulation changes upper limb cortical motor maps in dystonia

Neuronavigated robotic transcranial magnetic stimulation was used to investigate changes in upper limb muscle representation in a cervical dystonia patient before and at four time points up to 314 days after globus pallidus pars interna deep brain stimulation (GPi-DBS). GPi-DBS altered excitability and motor cortical representation of upper limb muscles; however, these changes were not associated with clinical improvement.

Genetic Mutations and Deep Brain Stimulation

Parkinson disease (PD) is a neurodegenerative disorder characterized by rest tremor, rigidity, bradykinesia, and postural instability. While most cases of PD are sporadic in nature, cases secondary to genetic mutations have been identified. These are typically monogenic and often present as early-onset or juvenile-onset PD. While rare, individuals with PD may harbor multiple pathogenic variants in PD-linked genes, potentially leading to more severe presentations. This chapter reviews available data regarding deep brain stimulation (DBS) targets and DBS outcomes in cases that are genetically proved to be PD. We report a patient with juvenile-onset PD whose course featured severe peak-dose dyskinesias and generalized off dystonias. Genetic testing supported a rare diagnosis of digenic PD, with homogenous deletions in PRKN (Parkin) and a single transition in PARK6 (PINK1). Bilateral DBS electrodes were implanted into the globus pallidus pars interna (GPi), leading to significant amelioration of both off and on symptoms.

Thalamic and extra-thalamic connections of the Globus Pallidus in the human brain: The ultradirect pathway

A dominant framework for understanding loss and recovery of consciousness, particularly in the context of severe brain injury, focuses on cortico-subcortical recurrent interactions, with a strong emphasis on excitatory thalamofugal projections. Recent work in healthy volunteers and patients, however, suggests a previously unappreciated role for the globus pallidus pars externa in maintaining a state of consciousness – a finding that is consistent with non-human animal work demonstrating the existence of direct (i.e., extrathalamic) pallido-cortical projections as well as their involvement in modulating electrocortical arousal and sleep. Leveraging on the high-quality Human Connectome Project dataset, we report for the first time in humans, in vivo evidence of (direct) pallido-cortical and pallido-thalamic projections, distinguishing between internal and external pallidal regions. Our data confirm, in humans, the existence of an “ultradirect” extra-thalamic pallido-cortical pathway, with the pars externa connecting preferentially, and extensively, to prefrontal cortex and the pars interna primarily connecting to sensorimotor cortical areas. Furthermore, we also report, for the first time in humans, the likely existence of a direct pathway uniting the globus pallidus pars externa and the medio-dorsal areas of thalamus often implicated in maintenance and recovery of consciousness. Consistent with the pallido-cortical connectivity results, the pars interna appeared to predominantly connect with the sensorimotor areas of thalamus. Collectively, these findings demonstrate the existence in humans of an extra-thalamic “ultradirect” pallido-cortical pathway and suggest a central role of the external segment of the globus pallidum in supporting consciousness.

Deep Brain Stimulation in Parkinson’s Disease: New and Emerging Targets for Refractory Motor and Nonmotor Symptoms

Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by bradykinesia, tremor, rigidity, and postural instability (PI), in addition to numerous nonmotor manifestations. Many pharmacological therapies now exist to successfully treat PD motor symptoms; however, as the disease progresses, it often becomes challenging to treat with medications alone. Deep brain stimulation (DBS) has become a crucial player in PD treatment, particularly for patients who have disabling motor complications from medical treatment. Well-established DBS targets include the subthalamic nucleus (STN), the globus pallidus pars interna (GPi), and to a lesser degree the ventral intermediate nucleus (VIM) of the thalamus. Studies of alternative DBS targets for PD are ongoing, the majority of which have shown some clinical benefit; however, more carefully designed and controlled studies are needed. In the present review, we discuss the role of these new and emerging DBS targets in treating refractory axial motor symptoms and other motor and nonmotor symptoms (NMS).