Physiological Effects of Botulinum Toxin Therapy in Primary Cervical Dystonia

Primary Cervical Dystonia (PCD) is the most common type of focal dystonia. In addition to pain, PCD is associated with disability in many activities of daily living; social stigma and embarrassment; and decreased quality of life. Botulinum toxin (BoNT) therapy is the "gold standard" for treatment of PCD. Although effective in improving dystonia symptoms, BoNT injections have been associated with suboptimal improvements and the benefits of BoNT may last shorter than the expected time frame of 12 weeks. PCD subjects are referred for deep brain stimulation surgery if there is poor or inconsistent response to medical treatment. In addition to the need for repetitive injections, subjects may suffer from side effects such as neck pain, muscle weakness, head drop, breathing difficulty, and swallowing issues. BoNT therapy outcomes are not likely to improve until and unless the investigators understand the underlying mechanisms of action.

The primary goal of this study is to examine the physiological effects of BoNT therapy and to advance the understanding of the pathophysiology of dystonia. BoNT therapy is commonly perceived to induce peripheral muscle weakness through inhibition of acetylcholine release at the neuromuscular junction. However many argue that this is not likely the only or primary mechanism of action, as many subjects have improvement in dystonia without discernible muscle weakness and others have significant weakness and no improvement in their dystonia. Indeed, BoNT has been proposed to induce central effects possibly related to modulation of the muscle spindle afferent feedback or a retrograde transport of toxin to the central nervous system. A leading theory underpinning the pathophysiology of dystonia is loss of motor inhibition (or increased excitability) at the level of the spinal cord, brainstem and the motor cortex. Thus, modulation of pathology in these central pathways is critical for control of dystonia. Transcranial magnetic stimulation (TMS) is a noninvasive physiological technique for assessment of motor cortex excitability. Paired-pulse TMS paradigms, such as short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are well established paradigms for evaluation of motor cortex excitability.

SICI is measured by delivering a subthreshold conditioning pulse prior to the suprathreshold test pulse at short interstimulus intervals (ISI) of 1-5 milliseconds (ms) resulting in a lower motor evoked potential (MEP) response to the test pulse. SICI is regarded as a gamma-aminobutyric acid A (GABA-A) receptor-mediated inhibition that involves activation of the cortical inhibitory interneurons. ICF is measured using a paradigm similar to SICI but with a longer ISI of 8-30 ms resulting in increase in MEP response. Glutamate is probably involved in producing ICF through cortical facilitation.

In focal dystonia, including PCD, there is failure of SICI recorded from hand muscles, and conversely, there is enhanced ICF recorded from hand muscles. These paradigms were not recorded from neck muscles as they are technically challenging. Nevertheless an important finding was noted that in PCD, the motor cortical inhibition is widespread and extends beyond the area of symptomatic muscles.

TMS was used to assess the effects of BoNT on SICI in subjects with arm dystonia. SICI in distal hand muscle increases at one month after BoNT injections and returns to the previously abnormal levels of excitability at three months. It can be speculated that the BoNT therapy to arm muscles modulates the afferent input from muscles, which probably results in reorganization of the motor cortex. It is not clear if the physiological change induced by BoNT therapy had any correlation with the clinical improvement. In addition, it is not clear if the change in motor cortex excitability ultimately affects the corticospinal drive to the dystonic muscles.