New clinical neuroscience technologies for treating neurodegenerative disorders
Wei-Peng Teo, Alicia M. Goodwill and Peter G. Enticott
The use of electricity and electromagnetism to probe neural activity and function has been described in fair detail even in ancient literature almost 2000 years ago (AD 43-48) (Ceccarelli, 1962). The earliest record for the use of electricity to treat ailments of the brain was by Scribonius Largus, Roman physician to the Emperor Claudius, who reported that placing a torpedo fish (a species of electric ray) over the heads of patients with headaches induced a transient period of stupor and analgesic effect. In a similar fashion, Muslim physician Ibn Sidah (AD 1007-1066) further suggested that placing a live electric catfish on the frontal bone of the skull may help to treat epilepsy (Kellaway, 1946). However, it was the work of Italian physician Luigi Galvani (de Micheli, 1991), who inadvertently discovered the phenomenon of ‘animal electricity’, and physicist Alessandro Volta (Pancaldi, 2003) that founded the field of electro-neurophysiology. Galvani’s nephew, Giovanni Aldini in 1804, was one of the first to report the successful treatment of patients suffering from melancholia by applying direct electrical current over the head. Aldini further assessed the effects of direct electric currents applied to himself and reported an unpleasant sensation followed by insomnia for several days.
In the last two decades, advances in our understanding of electro-neurophysiology have led to the development and refinement of both invasive and non-invasive forms of brain stimulation to treat psychiatric and neurodegenerative diseases. In the field of non-invasive brain stimulation, transcranial magnetic stimulation, or TMS, has become a standard tool to probe cognitive functioning. Based on Faraday’s law of electromagnetism, TMS is capable of stimulating cortical neurons so as to activate or inhibit specific regions of the brain (Ziemann, 2010). When applied repetitively with the appropriate pulse frequency, duration and intensity, repetitive TMS (rTMS) can exert a neuro-modulatory effect by which neural function and behaviour may be altered during (online) and after (offline) the stimulation period (Hallett, 2007; Thickbroom, 2007). Similar to TMS, another form of non-invasive brain stimulation, known as transcranial direct-current stimulation (tDCS), has in recent years received great attention (Nitsche et al., 2008; Tanaka & Watanabe, 2009). tDCS works by placing two electrodes (a positive anode and negative cathode in saline-soaked sponges) over the scalp of targeted brain regions. This method allows weak direct current (typically 0.5-2mA) to pass through the scalp from the cathode to anode non-invasively and safely to stimulate cortical regions of the brain. This effect of tDCS results in polarity-specific changes to brain activity (anodal/positive tDCS increases brain excitability; cathodal/ negative tDCS, inhibits brain excitability) (Nitsche & Paulus, 2000; Priori, Berardelli, Rona, Accornero & Manfredi, 1998) that may have a follow-on effect on motor and/or cognitive performance.
While non-invasive brain stimulation techniques are capable of modulating cortical brain regions, their effects on subcortical structures are limited. In this sense, invasive techniques such as deep brain stimulation (DBS) may be used to target known neurological pathologies that stem from subcortical deficits, such as Parkinson’s disease (PD). This procedure, while highly invasive in nature, produces almost immediate relief from PD-related motor symptoms such as resting tremors, muscle rigidity and gait disturbances. More recently, improvements in DBS therapy with the development of multi-directional electrical implant probes have a greater ability to deliver targeted, individualised DBS therapy to optimise treatment outcomes for people with PD.
While recent advances in non-invasive and invasive brain stimulation techniques have once again sparked renewed interest for its use to treat neurological and psychiatric disorders, its clinical efficacy and application are still unclear. In this chapter, we will highlight the current evidence for the efficacy of rTMS, tDCS and DBS as a treatment for neurodegenerative diseases. Further we will discuss some of the limitations with each method that may be used for future research and clinical considerations.
Transcranial magnetic stimulation in clinical neuroscience
Transcranial magnetic stimulation has emerged as a popular technique for treating physical, cognitive and behavioural symptomology in neurodegenerative disease. TMS is currently approved for treatment-resistant major depressive disorder (MDD) in many geographical locations including Australia, New Zealand, Japan, India, United States, Canada and Europe. Due to the non-invasive nature of this technique, scientists are continuing to uncover its therapeutic potential for relieving a range of symptoms in various neurodegenerative conditions, such as PD and Alzheimer’s disease (AD).
The principles of TMS are derived from Faraday’s law of induction, whereby a magnetic pulse is penetrated through the scalp perpendicular to a coil, eliciting a series of electrical currents. Traditional coils are circular or figure-of-eight in design, enabling widespread and more focal stimulation of brain regions respectively (Rossini et al., 2015). Newer HI coils have also been developed, which can penetrate deeper neuronal regions (Tendler, Bamea Ygael, Roth & Zangen, 2016). TMS can be delivered through single-pulse, paired-pulse or repetitive rhythmic stimuli. Single- and paired-pulse methods provide transient stimulation and are generally utilised for assessment of the corticospinal pathway. In contrast, rTMS modulates underlying neuronal activity that outlasts the stimulation period (Rossini et al., 2015), providing an environment for the induction of brain plasticity.
The desired outcomes from rTMS can be manipulated primarily through the stimulation frequency. Higher rTMS frequencies (> 5Hz) and intermittent theta-burst stimulation (iTBS) facilitate cortical excitability, whereas lower rTMS frequencies (< 1Hz) and continuous theta-burst stimulation (cTBS) suppress cortical excitability (Rossini et al., 2015). Animal models have also suggested a neuroprotective role of rTMS (Lu et al., 2017). Collectively, the ability to manipulate these parameters holds promise for individualising treatment and specifically targeting symptoms that result from altered cortical neurotransmission and neurodegeneration.
Repetitive TMS is safe, non-invasive and may come with less adverse effects than many available pharmacological treatments. The most commonly reported side-effects include mild headaches following stimulation and a tingling sensation on the scalp. There is also a small (0.1%) risk of experiencing a seizure, however, this risk is low in people without history of epilepsy and can be mitigated through appropriate screening and adherence to the current safety guidelines for frequency and intensity of stimulation (Rossini et al., 2015).
The first insights into the benefits of rTMS in people with PD began over 20-years ago (Pascual-Leone et al., 1994). Since then numerous reports have highlighted its potential as a non-invasive adjunct to conventional physical and pharmacological therapy. The cardinal motor signs of PD can be examined via the United Parkinson’s Disease Rating Scale subscale III (UPDRS III) and have been the most studied outcomes following rTMS. Pooled data from over 636 patients has showed improved UPDRS III scores (Goodwill et al., 2017; Xie et al., 2015) and gait (Goodwill et al., 2017) following both high- and low-frequency rTMS over the primary motor, supplementary motor and premotor cortical brain regions. The most recent large-scale clinical trial demonstrated the efficacy of high-frequency rTMS over bilateral motor cortices to improve bradvkinesia and rigidity, but gait and tremor remained unchanged (Brys et al., 2016). This finding is perhaps expected considering the differing pathophysiology underpinning hypo- and hyperkinetic symptoms observed in PD. In this context, facilitated cortical excitability through the application of high-frequency rTMS may compensate for reduced output from the basal ganglia to motor cortical areas that plan and initiate voluntary movement.
Low-frequency rTMS has the potential to target hyperkinetic symptoms of PD and reduce neurodegeneration (Dong et al., 2015). Several studies have shown low-frequency rTMS to be effective in relieving levodopa-induced dyskinesias
(Filipovic, Rothwell, van de Warrenburg & Bhatia, 2009; Sayin et al., 2014; Wagle- Shukla et al., 2007) and improving hand dexterity (e.g. buttoning up clothes) (Ikeguchi et al., 2003), however changes on the UPDRS scale have been variable (Filipovic, Rothwell & Bhatia, 2010; Shimamoto et al., 2001).
Despite majority of the research regarding rTMS and PD focusing on motor symptoms, cognitive and mood disturbances, which are observed in up to 50% of people with PD (Cosgrove, Alty & Jamieson, 2015; Reijnders, Ehrt, Weber, Aarsland & Leentjens, 2008), may also benefit from this type of brain stimulation. Pooled data from 312 patients showed high-frequency rTMS improved depression on two clinical scales, to a similar magnitude as that observed from antidepressant selective serotonin re-uptake inhibitors (Xie et al., 2015). Following that report, two large randomised controlled trials have also demonstrated high-frequency rTMS over the motor cortex and dorsolateral prefrontal cortex effectively reduced depressive symptoms in people with PD (Makkos et al., 2016; Shin, Youn, Chung & Sohn, 2016). There is currently insufficient evidence in support of rTMS on cognition in PD (Goodwill et al., 2017). Of the few published studies, most have reported no marginal improvements in neuropsychological performance (Benninger et al., 2012; Sedlackova, Rektorova, Srovnalova & Rektor, 2009) or mild cognitive impairment (Buard et al., 2018) following high-frequency rTMS over the motor and/or dorsolateral prefrontal cortex.
In addition to cognitive dysfunction associated with PD, rTMS has been identified as an efficacious therapy for people with mild cognitive impairment and AD. While its intended use is not to provide a cure, rTMS can modulate cortical networks in specific areas of cognitive processing and has been beneficial in improving cognitive functioning in patients with mild-moderate AD (Cheng et al., 2018). rTMS may also exert neuroprotective properties which aim to slow the progression of cognitive decline in people with AD, through upregulating brain-derived neurotrophic factor (BDNF) within the hippocampus (Yulug et al., 2017).
In a number of randomised controlled trials in AD, high-frequency rTMS applied over the dorsolateral prefrontal cortex improved naming ability (Cotelli, Manenti, Сарра, Zanetti & Miniussi, 2008), global cognition (Alcala-Lozano et al., 2018; Zhao et al., 2017), episodic memory and verbal learning (Zhao et al., 2017) and activities of daily living (Ahmed, Darwish, Khedr, El Serogy & Ali, 2012). Preliminary evidence has also shown that these improvements in cognitive functioning can be retained up to a month post-treatment (Alcala-Lozano et al., 2018). Longitudinal research is required to determine whether rTMS can be used to prevent cognitive decline and conversion from mild cognitive impairment to AD.
Repetitive TMS can also be applied as an adjunct to other therapeutic techniques, such as cognitive training (Bentwich et al., 2011; Nguyen et al., 2017; Rabey & Dobronevsky, 2016). Improvements on the Alzheimer’s Disease Assessment Scale following high-frequency rTMS and cognitive training were also comparable to the magnitude of improvement seen from cholinesterase inhibitors (Bentwich et al., 2011). In some patients, improvements in cognition following high-frequency rTMS have lasted from up to nine to 12 months following stimulation (Nguyen et al., 2017; Rabey & Dobronevsky, 2016), however retention may be unique to strong rTMS responders (Nguyen et al., 2017). Of note is the absence of control groups in these previous studies, which makes it difficult to distinguish whether the benefits are due to rTMS, cognitive training, the concurrent application of these techniques, or placebo effects. This promising evidence should be confirmed in larger randomised controlled trials.
Repetitive TMS has also been shown to improve other neuropsychological symptoms in AD. rTMS applied concurrent with antipsychotic medications resulted in improved cognition, behavioural and psychological symptoms (Wu et al., 2015). Moreover, in patients with mild cognitive impairment, high-frequency rTMS improved apathy symptoms, which is a predictor of conversion to AD (Padala et al., 2018). This preliminary evidence highlights the potential for rTMS to be utilised as a preventative technique in the early stages of mild cognitive impairment, which could delay or prevent the conversion to full-blown AD.
There is preliminary evidence regarding the benefits of rTMS to improve symptoms in multiple sclerosis (MS). MS is characterised by demyelination of nerve fibres and impaired neurotransmission; accordingly, most of the research has utilised high-frequency rTMS to target motor symptoms. In early small-scale studies, high-frequency rTMS over the motor cortex reduced spasticity (Centonze, Koch et al., 2007) and urinary dysfunction (Centonze, Petta et al., 2007), while improving hand dexterity (Koch et al., 2008) and working memory (Hulst et al., 2017). There are also reports of deep rTMS and iTBS reducing fatigue (Gaede et al., 2018) and spasticity, respectively (Mori et al., 2010). rTMS has also been prescribed as an adjunct to exercise therapy in this population, with reports of concurrent iTBS and exercise therapy yielding greater improvements in spasticity symptoms, physical function and quality of life than either modality alone (Mori et al., 2011).
There is insufficient available data to draw conclusions about the efficacy of rTMS in other neurodegenerative conditions such as motor neuron disease (MND) and Huntington’s disease. Two case-reports have documented improvements in Huntington’s disease-related chorea symptoms (Berardelli & Suppa, 2013) and anxiety, memory and physical pain (Davis, Phillips, Tendler & Oberdeck, 2016). Two small studies in people with ALS have reported modest-to-insignificant slowing of decline on the Amyotrophic Lateral Sclerosis Deterioration Scale following cTBS (Di Lazzaro et al., 2006, 2009), while high-frequency rTMS improved maximal strength and quality of life. Considering the lack of treatment or cure for these conditions, ongoing investigation into the benefits of rTMS to manage symptoms in these populations is warranted.
rTMS is a promising therapeutic tool that can be utilised alongside traditional physical and pharmological therapies to manage physical, behavioural and cognitive symptoms in neurodegenerative conditions such as PD and AD. Given the inherently large variability in outcomes following rTMS, individually prescribed protocols are needed to maximise the efficacy and clinically utility of this technique.