New research from Baylor College of Medicine scientists shows that a combination of deep brain stimulation (DBS) and exercise has potential benefits for treating ataxia, a rare genetic neurodegenerative disease characterized by progressive irreversible problems with movement.
Working with a mouse model of the human condition, researchers at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital discovered that combining DBS targeted to the cerebellum, a major motor center in the brain, and exercise rescued limb coordination and stepping and that the benefits persisted without further stimulation.
In addition, the study reports that stimulating mice with early-stage ataxia showed the most dramatic improvements. These and other findings, published in the journal Nature Communications, provide valuable new insights in designing future DBS strategies to treat the human condition.
“People with ataxia usually have progressive problems with movement, including impaired balance and coordination that affect the person’s ability to walk, talk and use fine motor skills. There are limited treatment options for this condition, and patients typically survive 15 to 20 years after symptoms first appear,” said first author Lauren Miterko, a graduate student in Dr. Roy Sillitoe’s lab at Baylor.
DBS currently is used to relieve motor dysfunction in Parkinson’s disease and other movement conditions, but its value in treating ataxia has not been extensively explored.
In this study, the researchers worked with Car8, a mouse model of hereditary ataxia to investigate whether adjusting the parameters of DBS and the stimulation target location would help increase the treatment’s efficacy for the condition.
Frequency matters
“We first targeted the cerebellum, because it’s a primary motor center in the brain and this target location for DBS has seen encouraging success for treating motor problems that are associated with other conditions, such as a stroke,” Miterko said.
“We systematically targeted the cerebellum with different frequencies of DBS and determined whether there was an optimal frequency that would boost the efficacy of the treatment. When we used a particular frequency, 13 Hz, that was when motor function improved in our Car8 mice.”
DBS plus exercise improved the outcomes
Neurostimulation with DBS improved muscle function and the general mobility of Car8 mice, but the researchers looked for additional ways to improve the condition.
“We know that exercise in general can benefit both muscle and neuronal health, and previous work in Parkinson’s disease and stroke patients mentioned that neuromodulation techniques combined with physical stimulation showed benefits, so we decided to include exercise in our investigation,” Miterko said.
“We found that when the animals received DBS during exercise on a treadmill, there were improvements in motor coordination and stepping that we had not observed with DBS alone.”
“In our ataxia model, improvements did not go away after one week of treatment, which has important practical implications for potential clinical applications,” said co-author Dr. Meike E. van der Heijden, postdoctoral associate in the Sillitoe lab. “Also, all young mice with early stage ataxia responded, suggesting that it is possible that early treatment also might provide the biggest benefit for patients in the future.”
The researchers also gained insights into the type of brain cells involved in the process of restoring movement in this ataxia mouse model. They found that Purkinje cell neurotransmission is needed for DBS to be effective. Purkinje cells are a type of neuron located in the cerebellar cortex of the brain. These cells are involved in the regulation of movement, balance and coordination among other functions.
“We are particularly excited about the results of this study because it may be possible to extrapolate our approach for treating not only other motor diseases, but perhaps also non-motor neuropsychiatric conditions,” said corresponding author Dr. Roy Sillitoe, associate professor of pathology and immunology and neuroscience at Baylor College of Medicine, and director of the Neuropathology Core facility at the Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital.
Cerebellar Ataxia
Cerebellar tDCS can modulate the excitability of Purkinje cells in the cerebellar cortex and hence modify the cerebellar output via the cerebello-thalamo-cortical pathway. A polarity-specific effect has been shown in different studies. Anodal ctDCS increases the excitability of Purkinje cells of the cerebellar cortex, augmenting the inhibitory effects of the cerebellar cortex on the deep cerebellar nuclei and, hence, reducing the cerebello-thalamic facilitatory drive to the cortical areas (Grimaldi et al., 2014a, 2016; Maas et al., 2020).
An initial study by Grimaldi and Manto (2013) failed to show any significant effect of cerebellar anodal tDCS on upper limb coordination and posture. However, anodal ctDCS (1 mA, 20 min) reduced the amplitudes of long-latency stretch reflexes. Subsequently, in a separate study by the same group, a beneficial effect of the cerebello-cerebral tDCS (tCCDCS; 1 mA, 20 min on each site) has been demonstrated on upper limb tremor (postural and action) by power spectral density analysis. tCCDCS reduced the onset latency of the antagonist activity associated with fast goal-directed movements toward three aimed targets (Grimaldi et al., 2014b). Hence, tCCDCS modified the delayed-onset braking action of antagonist activity that results in hypermetria in cerebellar ataxia.
A transient beneficial effect of single-session ctDCS (2 mA, 20 min) on degenerative cerebellar ataxia has been demonstrated by Benussi et al. (2015). Subsequently, in a different crossover study by the same group, they have demonstrated long-term effects of anodal ctDCS using stimulation for 5 days/week for 2 weeks (Benussi et al., 2017b).
Recently, they have also used cerebello-spinal tDCS with anodal cerebellar and cathodal spinal stimulation. CBI was measured using TMS. Statistically significant beneficial effects were seen in short term (2 weeks) and long term (3 months). The benefit is likely due to the combined effect of CBI by anodal ctDCS and influence on the ascending and the descending spinal pathways on spinal reflex excitability and functional neuroplastic changes by spinal cathodal tDCS (Benussi et al., 2018).
The results of a similar trial with 2 weeks of anodal ctDCS in patients with spinocerebellar ataxia type 3 are awaited (Maas et al., 2019). An improvement of marked postural tremor in cerebellar ataxia associated with ANO10 mutation was noted with cerebello-cerebral stimulation (anode over cerebellum and cathode over M1, 1.5 Ma, 20 min) (Bodranghien et al., 2017). No significant beneficial effect was noted with anodal tDCS to the cerebellum or the motor cortex in grip force control (2 mA, 25 min) (John et al., 2017) or force-field reaching adaptation (2 mA, 22 min) (Hulst et al., 2017) in patients with cerebellar ataxia.
A beneficial effect of combined intensive rehabilitation program (IRP) and cerebello-cerebral tDCS was seen in patients with Friedreich’s ataxia. IRP consisted of two sessions/day for 5 weeks, and tDCS (2 mA, 20 min) was applied once/day for 2 weeks. tDCS can facilitate the rehabilitative interventions, likely by improving the recruitment activity at the pyramidal cell layer on the M1 with subsequent neural network function recovery (Vavla et al., 2019).
A similar positive effect was noted in home-based chronic stimulation with remotely supervised anodal ctDCS (2.5 mA, 20 min, 60 sessions) with cognitive and physiotherapy in an elderly female with progressive cerebellar ataxia (Pilloni et al., 2019).
We believe that there is a huge scope of using tDCS in degenerative cerebellar ataxia where practically no therapeutic options are available. Isolated cerebellar stimulation, or in combination (cerebello-cerebral and cerebello-spinal), can be offered in ataxic patients. A concurrent rehabilitation program may boost the therapeutic benefit.
Transcranial Pulsed Current Stimulation
While anodal-tDCS modifies neuronal excitability by tonic depolarization of the resting membrane potential, anodal-tPCS (a-tPCS) modifies neuronal excitability by a combination of tonic and phasic effects. The tonic effects of a-tPCS are related to the net direct current component, leading to the tonic depolarization of the resting membrane potential.
The phasic effects of a-tPCS are due to the on/off nature of pulsatile currents. In tPCS, the current flows in unidirectional pulses separated by an IPI, in contrast to the continuous flow of direct current in tDCS (Fitzgerald, 2014; Jaberzadeh et al., 2015). tPCS can be applied with short inter-pulse intervals (tPCSSIPI) or long inter-pulse intervals (tPCSLIPI).
Jaberzadeh et al. (2014) tested four testing conditions: a-tDCS, a-tPCSSIPI (IPI 50 ms), a-tPCSLIPI (IPI 650 ms), and sham a-tPCSSIPI. They have noted that only anodal tDCS and anodal tPCSSIPI over M1 increase the corticospinal excitability in healthy individuals, lasting for at least 30 min. The increase in CSE was larger with a-tPCSSIPI.
The effect of tPCS (with a commercially available tPCS device—Fisher Wallace model FW 100-C, New York) with treadmill walk has been evaluated in PD patients, with focus on gait and balance. The tPCS session increased gait velocity and stride length significantly compared with treadmill or tPCS + treadmill. The number of steps needed to recover balance decreased after tPCS and tPCS + treadmill (Alon et al., 2012).
The intensity-specific modulation of cortical excitability by tPCS has been addressed recently by Ma et al. (2019). Enhancement of cortical excitability by low-intensity anodal tPCS is likely related to astrocytic Ca2+ elevations due to the noradrenergic activation of alpha-1 adrenergic receptors, but high-intensity anodal tPCS decrease cortical excitability with excessive calcium activity in neurons.
The role of tPCS in other disorders like ataxia, where gait and balance are predominantly affected, has not been studied to date.
Conclusion
The results of tES studies in movement disorders are encouraging, but their utility in the mainstream treatment of movement disorders is still limited. Because of the heterogeneity of patient population and the diversity of the protocols used in these studies, it is hard to do a systemic review and to quantify the actual therapeutic benefit of different modes of tES. The majority of trials are not double-blinded and the level of evidence of efficacy and safety is unknown.
These are the major limitations for reviewing different modes of tES. So far, tDCS is the most commonly used technique. In the field of movement disorders, tDCS has been tested mostly for different aspects of PD (22 studies targeting gait and balance, 10 studies evaluating upper limb motor function, seven studies for cognitive function, and one study each for pathological gambling, speech, sleep, fatigue, and dyskinesia).
The efficacy of tDCS has also been tested in dystonia and cerebellar ataxia (11 studies for each), but the number of studies for other movement disorders like ET, OT, HD, MSA, PSP, and CBS is quite less. Anodal tDCS over motor cortex in PD, over cerebellum in ataxia (±simultaneous cathodal spinal stimulation) and cathodal tDCS over motor cortex in dystonia, has shown beneficial results. Modifying a complex dysfunctional network by acute stimulation seems unlikely.
Chronic stimulation for at least 2 weeks seems to be a safe and rational approach. Other techniques like tACS, tPCS, and tRNS are less well studied in movement disorders. As tACS has been proposed to entrain brain oscillations, it can be used as a tool to assess and modulate the complex tremor network. Recently, cross-frequency phase-amplitude coupling is an evolving pathophysiology for the OFF and the ON state of PD, which further expands the scope of tACS in PD.
So far, tACS has been evaluated in PD (three studies), enhanced physiological tremor (two studies), and cervical dystonia (two studies). In contrast, tPCS and tRNS are relatively new in the field of movement disorders. Due to its combined phasic and tonic effects, tPCS can be an effective and more tolerable therapy in PD or ataxia. The role of tRNS with a wide range of frequency should also be evaluated further in movement disorders.
Newer technologies like quantitative electroencephalography, better circuit design for stimulation devices, and programmability of stimulation parameters are all necessary to move this field forward. Elucidating the precise patterns of network dysfunction in a highly connected system is another important engineering problem that has to be directly tackled by novel signal processing methods.
It may only then be possible to target the precise individualized sites in specific patients with specific diseases for stimulation. Considered together, this emerging field of individualized dysfunction measurement and device optimization for portable non-invasive stimulation for movement disorders will be the next frontier of tES.
In the literature, there are mostly segregated case reports and reviews on tES. In them, mostly tDCS has been focused, while other modes are neglected. There is no literature combining all the modes of tES together so far. In this review, we have highlighted the basic concept of the different modes of tES and have summarized the studies done so far on the therapeutic benefit of tES in movement disorders. We have also tried to find out the electro-physiological basis of the effect of each of these techniques.
There still remain some unanswered questions: (de Schipper et al., 2018). What are the detailed electrophysiological bases of the different modes of tES and are they sufficient enough to alter the complex brain network of movement disorders? (Schirinzi et al., 2018). Are there any methods like quantitative EEG, ligand-bound imaging, etc., to probe into the network for planning individualized tES? (Benito-León et al., 2015).
Is there any threshold of neurodegeneration beyond which applying tES is not reasonable? (Wu et al., 2018). What would be the realistic expectation after tES? (Falcon et al., 2016). How long does the effect of stimulation last? (Latorre et al., 2019). How feasible is supervised home-based chronic stimulation by patients themselves and is there any scope of adaptive tES as per patient need?
Large clinical trials with each of the stimulation technique, precisely targeting the individualized brain network, may help us to find some of the answers and thus will help to set up a standardized protocol for each of them.
reference link: https://www.frontiersin.org/articles/10.3389/fnins.2020.00522/full
More information: Lauren N. Miterko et al, Neuromodulation of the cerebellum rescues movement in a mouse model of ataxia, Nature Communications (2021). DOI: 10.1038/s41467-021-21417-8
