RTMS Treatment For Parkinson's Disease


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Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by degradation of dopamine-producing cells in the Substantia Nigra Pars Compacta.[1] The resulting decrease in dopamine produces motor symptoms characterized by resting tremor, bradykinesia, rigidity, mobilization difficulties, and balance deficits.[2] In addition to motor symptoms, PD also includes non-motor symptoms including cognitive impairment, depression, hallucinations, autonomic features and sleep problems.[3] PD affects all races and ethnicities, and it is estimated that 6-10 million people worldwide are afflicted by the disease.[2] The incidence of PD ranges from 10–18 per 100 000 person-years, and increases rapidly with age, affecting approximately 2-3% of the population older than 65 years of age.[1] Clinical Diagnosis of PD is based on the presence of typical parkisonian motor symptoms, including bradykinesia plus rigidity and resting tremor.[1] Current medical therapy for PD only treats the symptoms of the disease, and primarily consists of medications which slow or stop the underlying neurodegenerative process.[1] However it is reported that most patients develop complications after 5 years, including dyskinesia and motor fluctuations.[3] Novel treatments of PD have been emerging over the past decades, including Transcranial Magnetic Stimulation (TMS) which has generated interest as a potential therapeutic intervention.[2]

Transcranial Magnetic Stimulation (TMS)

Transcranial magnetic stimulation (TMS) was developed in 1985 by Barker and colleagues which allowed them to non-invasively stimulate areas of the human cortex of the brain.[4] Since then, this technology has developed and found a place in both clinical research and treatment of various populations such as those experiencing mood[5] or movement disorders [6]. This modality is comprised of numerous conductive wires wrapped together into a circular coil within a hard plastic housing. By passing a brief electric pulse through these coil windings, a magnetic field is generated perpendicular to the coil which passes relatively unimpeded through the scalp and skull when placed on the head. This magnetic pulse, by the principles of electromagnetism, produce secondary electric fields in the opposite direction to the field generated by the coil.[4][7][8][9] It is these secondary fields that influence any conductive material or tissue in the path of the magnetic field. In this case, that conductive tissue is neurons within the cortex of the brain. Using the above phenomenon, TMS can be used to stimulate or excite regions of the cortex to probe the function of various brain regions and their interactions.[2][9][10]

Types of TMS

  1. Single pulse TMS can be used to simply stimulate a given area while recording the output and is commonly used in research where an area such as the motor cortex is stimulated and a motor response can be recorded from muscles of the body via electromyography.[7][9]
  2. Paired-pulse TMS can be used to assess the effect of a preceding stimulus on a secondary stimulus.[11] While this technique is also primarily used in research, it allows for the assessment of one brain region on another. For example, a TMS pulse delivered to the motor cortex of one hemisphere of the brain 10ms prior to a TMS pulse delivered over the opposite motor cortex results in an inhibitory effect in motor output to the arms, showing firing patterns that allow for unimanual control of the upper limbs.[12][13]
  3. Repetitive TMS (rTMS) techniques involve stringing a large number of consecutive TMS pulses together in rapid succession. This method is used both in research and clinically as it can produce changes in cortical activity that last beyond the duration of the TMS protocol.[2][10][14] With some reports demonstrating excitability changes persisting for a number of hours[15]. The rate of pulse delivery appears to dictate the effect of the rTMS protocol, whereas those that deliver pulses at rates of >5Hz (high frequency rTMS) tend to produce excitatory effects and those delivered at rates of < 1Hz (low frequency rTMS) tend to produce inhibitory effects in the brain.[8][10]. These rTMS techniques have been approved as a treatment modality for those with non-responsive major depression disorder (MDD) in Canada.[5] While the use of rTMS has not yet been approved for clinical use in the treatment of movement disorders such as stroke, spinal cord injury,, and PD, the scientific literature suggests that it may provide some benefit to both motor and cognitive symptoms in these populations.[6][16][17][18]

Potential Benefits of RTMS for Individuals with Parkinson's Disease

Motor Benefits

Recent studies have shown that rTMS has a positive effect on motor functioning in patients with PD. Most studies have assessed motor outcomes in PD such as the UPDRS III in addition to various motor tasks such as gait or hand function with the use of rTMS treatments.[19][20] [21][22][23][24][25][26]. The cumulative results of such investigations reveal that high frequency rTMS delivered over motor areas of the cortex (both primary and supplementary motor areas) tend to improve motor scores on the UPDRS III following frequent sessions (ranging from daily to one session per week) of treatment [19][21][23][24][26] and with some observations showing maintenance of improvements for up to a month after treatment cessation.[20][22] The benefits seen were almost always observed with regard to bradykinesia or dyskinesia scores. Changes in gait have also been shown to result from  rTMS treatment such that gait speed improved after a single session of high frequency rTMS as assessed using the Timed Up and Go test.[25] Further, gait speed improvements were reported in conjunction with reductions in bradykinesia following rTMS treatments twice a week over the course of a month that persisted for at least a month following intervention.[21]Notably, one study examined frequent high frequency rTMS delivered to the primary motor cortex and tracking changes in functional MRI activity.[26] This group demonstrated that reductions in bradykinesia occurred following 12 weeks of weekly rTMS treatment and the amount of improvement was linked to increased activity within the caudate nucleus of the basal ganglia during motor task execution, suggesting that prolonged stimulation may induce plastic changes to subcortical structures of the brain.[26] Therefore, the use of high frequency rTMS appears to provide benefits to motor symptoms in PD as measured by the UPDRS III and in gait parameters.

The benefits of rTMS on motor function in PD is further supported by recent meta-analyses summarizing the controlled trials completed to date.[2][18] Specifically, gait performance (SMD = 0.70 ) and UPDRS III scores (SMD = 0.37) improved with rTMS treatment compared to sham stimulation, while improvements in hand function were not affected by rTMS.[2][18] One meta-analysis found that the mean change in UPDRS III scores with rTMS treatment was -6.42 points[2], corresponding to a clinically significant change.[27] These changes appear to depend on the location of rTMS stimulation, whereby high frequency rTMS over the primary motor cortex and low frequency rTMS over the supplementary motor area both resulted in motor improvements.[2][18] These effects of rTMS treatment showed no significant effects of medication or disease severity.[18] This suggests that rTMS may be an effective treatment for management of motor symptoms regardless of medication or disease severity.

Cognitive Benefits

A study conducted by Moisello et al. (2015) found that high frequency rTMS over the primary motor cortex enhanced retention of a visuo-motor skill (target reaching using proprioceptive cues) and memory consolidation in patients with PD.[28] Further, it has been shown that patients with PD receiving high frequency rTMS showed improved performance on the Stroop and Hooper and Wisconsin Tests, indicating that rTMS may help PD with dual-tasking and attention.[29] However, rTMS does not appear to have pronounced effects on other executive functions (e.g., visuospatial abilities, psychomotor speed) compared to sham stimulation although very limited study in this area has been conducted to date.[18] In a recent systematic review there was conflicting evidence that rTMS was effective in being used for patients with PD and depression.[30] However, one study carried out on a small cohort of PD patients reported significant benefit from rTMS, evidenced by significant reductions in scores on the Hamilton Rating Scale for Depression and the Montgomery‐Asberg Depression Rating Scale, but not on the Beck Depression Inventory, compared with sham treatment.[31] Therefore, rTMS may provide some cognitive and mood benefits, but the resulting changes are likely small and not clinically significant.

Additional Resources

References

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