More than 180 years ago, James Parkinson first described the disorder that bears his name, and 30 years ago levodopa, still the most effective therapy, was introduced. Parkinson's disease is a neurodegenerative disorder of unknown cause that affects over 1 million people in North America. Age is the single most consistent risk factor, and with the increasing age of the general population, the prevalence of Parkinson's disease will rise steadily in the future. The impact of the disease is indicated by the fact that mortality is two to five times as high among affected persons as among age-matched controls,¹– . . .

Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.)

PathophysiologyThe establishment of a model of parkinsonism through the administration of MPTP to nonhuman primates has provided important insights into new therapeutic strategies. A typical parkinsonian syndrome develops in the animals that is characterized by dopaminergic-cell loss in the substantia nigra and striking abnormalities in the spontaneous activity and sensorimotor responses of neurons in the basal ganglia.^94,95 A fundamental discovery has been that the dopamine-deficiency state is associated with increased activity of the inhibitory γ-aminobutyric acid (GABA)–employing (GABAergic) output nuclei in the basal ganglia, the internal segment of the globus pallidus, and the pars reticulata of the substantia . . .