Neuronal activity and outcomes from thalamic surgery for spinocerebellar ataxia

Abstract

ObjectivesWe investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia.MethodsFive patients with SCA with cortical atrophy (ages 60‐69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57–71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET.ResultsPostsurgery mean scores for the Fahn–Tolosa–Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%).InterpretationThalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello‐thalamo‐cortical network.

Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

“…13 A full-body tremor could seemingly result in an increase in our ataxia measure. It seems unlikely that the complex millisecond-timescale computations performed by Purkinje cells required for very fine motor control-enabling, say, piano performance-can be recovered through electrical stimulation.…”

“…Finally, we must note that it is, of course, difficult to fully differentiate tremor from ataxia, as previous groups studying potential DBS therapies have noted. 13 A full-body tremor could seemingly result in an increase in our ataxia measure. However, comparison of the tremor versus ataxia plots in both Figures 2 and 3 clearly indicates that the tremor and ataxia measures are independent, as they evolve quite differently with age and frequency of stimulation.…”

“…12,13 We propose that it may be possible to treat tremor through a wide set of stimulation locations and parameters, whereas improving coordination is more difficult. 12,13 We propose that it may be possible to treat tremor through a wide set of stimulation locations and parameters, whereas improving coordination is more difficult.…”

“…Previous studies in ataxia patients showed that thalamic and basal ganglia stimulation improved cerebellar tremor, without consistently improving gait ataxia. 12,13 We propose that it may be possible to treat tremor through a wide set of stimulation locations and parameters, whereas improving coordination is more difficult. Inspired by the ideas that essential tremor depends on interplay across many oscillatory regions and may represent an intermediate state of Purkinje cell degeneration, 42 we propose that Purkinje cell misfiring and loss dysregulate the cerebellothalamocortical network, allowing oscillatory propagation through the network.…”

“…DCAs have numerous etiologies, Mendelian and sporadic. Whereas previous work assessed thalamic and basal ganglia stimulation to treat DCAs, 12,13 we targeted stimulation to the dorsal dentate nucleus, because the dentate is immediately downstream from Purkinje cells; furthermore, as the primary cerebellar motor output, it processes the majority of deep cerebellar motor control information. Therapeutic approaches vary, 4 but they typically fail to sufficiently alleviate symptoms.…”