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Motor problems in Parkinson’s disease: fluctuations, gait, balance and falls
Published in Jeremy Playfer, John Hindle, Andrew Lees, Parkinson's Disease in the Older Patient, 2018
Helen Roberts, Peter Overstall
Motor problems in PD are associated with altered activity in the cortico-basal ganglia-thalamo-cortical loop, thus surgical manipulation at various sites within this closed loop can affect the clinical state. Neurosurgery is usually reserved for patients with advanced disease suffering from motor fluctuations and dyskinesias, or those with isolated severe tremor. Most surgery aims to reduce abnormally increased neuronal activity through thermo-ablation, deep-brain stimulation (DBS), or – less commonly – gamma knife radiation (associated with difficulty with lesion size and accuracy and radiation necrosis). The main target sites are the following.
Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia
Published in Expert Review of Neurotherapeutics, 2021
Benjamin J. Dorfman, Joohi Jimenez-Shahed
Dopaminergic dysfunction is implicated in numerous psychiatric and neurologic disorders. The presence of multiple pathways with varied functions makes the dopaminergic system notoriously complex and sensitive to a variety of derangements. Dopamine signaling in the basal ganglia facilitates movement through action selection, and alterations in dopamine signaling (e.g., dopamine supply or receptor availability) may manifest as a movement disorder [1–3]. Movement disorders may be classified as hyper- or hypokinetic, reflecting the degree of excitation of the final connections in the cortico-basal ganglia-thalamo-cortical loop, and are theorized to be determined in large part by the relative balance of the direct and indirect basal ganglia pathways, in which dopamine signaling plays a crucial role. Thus, relatively greater activity within the direct pathway yields a hyperkinetic movement disorder, whereas greater activity in the indirect pathway yields a hypokinetic disorder [1–3]. Depending on the neurologic condition, treatment with anti-dopaminergic versus dopaminergic medications, respectively, may serve to correct these imbalances and restore normal movements [1]. Psychiatric disorders related to aberrant dopamine signaling outside the basal ganglia are frequently treated by dopamine receptor blockade [3]. Use of a dopamine receptor blocking agent (DRBA) may acutely cause hypokinetic movement disorders (i.e., drug induced parkinsonism) as an AE, but long-term use may cause a hyperkinetic disorder (i.e., tardive syndromes) due to physiologic changes at the synapse [3].
Current and emerging pharmacotherapy for the treatment of adult attention deficit hyperactivity disorder (ADHD)
Published in Expert Opinion on Pharmacotherapy, 2019
Giulio Perugi, Alessandro Pallucchini, Salvatore Rizzato, Vito Pinzone, Pietro De Rossi
Although adults with co-occurring ADHD, ASD traits, tic disorders, and obsessive-compulsive symptoms are not uncommon in clinical practice, the treatment of these clinical conditions is very problematical. In some individuals, tics and/or other repetitive behaviors may worsen with stimulant drugs [146]. This mechanism happens when the stimulant drug increases the internally directed focus on premonitory tic urges, poorly filtered sensations, obsessions, and ruminations, causing the so-called zombie effect. This latter can be defined as a reduction of spontaneity, reactivity to external stimuli and empathy [147]. It is interesting to note that an alteration of the tonic and phasic dopaminergic system at the level of the cortico-basal ganglia-thalamo-cortical loop [148] can be impaired by the use of drugs blocking D2 receptors, often used to reduce the tics. Within this framework, antipsychotics may increase the propensity to learn tics (and worsen premonitory impulses) through the phenomenon of super-sensitivity of D2 receptors [149]. Some authors have also suggested that low doses of dopamine agonists could decrease both phasic and tonic dopamine and thus reduce both tic learning and expression.
Subthalamic nucleus deep brain stimulation for Parkinson’s disease: current trends and future directions
Published in Expert Review of Medical Devices, 2020
Antonella Macerollo, Ludvic Zrinzo, Harith Akram, Thomas Foltynie, Patricia Limousin
Short-lasting stimulation was utilized prior to ablative surgery to confirm targeting accuracy. With the development of commercially available implantable stimulators, the benefit of chronic high-frequency stimulation was established in 1987 by Benabid et al. after using electrical stimulation during a thalamotomy for essential tremor to confirm targeting accuracy [10]. It was observed that using stimulation at frequencies higher than 100 Hz led to immediate and reversible cessation of tremor. The authors proposed that, in order to avoid the significant side effects from bilateral thalamotomies, a thalamotomy for the most disabled side and chronic high-frequency DBS for the other side could be carried out [11]. The practical observation of these reversible and adaptable effects of high-frequency stimulation, which mimicked the effect of a lesion in the same place, was therefore the historical starting point of the modern development of DBS as a new method. In that early juncture, DBS of the Ventral intermediate (Vim) nucleus of the thalamus initially became the only target to treat essential tremor and parkinsonian tremor [12]. The role of the thalamus in the basal ganglia network has been very well known since the late 1980 s [13]. Indeed, the classic model of the basal ganglia has been established on the presence of intrinsic direct and indirect pathways, both comprising a set of excitatory glutamatergic and inhibitory GABAergic projections. In this model, cortical projections are directed to the striatum, which further converge on GPi and SNr (substantia nigra pars reticulata) either directly or indirectly via GPe and STN. The output from GPi and SNr is then directed to the thalamus, which further projects back to the cortex, forming a complete cortico-basal ganglia-thalamo-cortical loop. Both direct and indirect basal ganglia pathways are modulated by endogenous dopamine release from the SNc (substantia nigra pars compacta) [14].