Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study
Introduction
Over five million Americans have Alzheimer's disease (AD) and the lack of effective treatments has prompted research on prevention of dementia. Mild cognitive impairment (MCI), a prodrome of dementia is an attractive target for dementia prevention studies. The prevalence of MCI increases with age ranging from 16% to 20% among those aged 60 years and older and 29% in those aged 85 years or older (Lopez et al., 2003, Roberts and Knopman, 2013). The rates of conversion of MCI to AD vary from 10% to 30% annually (Morris and Cummings, 2005, Petersen et al., 1999). Given the wide range of AD conversion, research has focused on phenotypes of MCI known for higher rates of conversion to AD. The presence of behavioral problems increases the rate of conversion to AD. One key behavioral problem tipping the trajectory of neurodegeneration is apathy.
Apathy is a common and disabling behavioral concomitant of neurodegeneration such as Mild Cognitive Impairment (MCI) and Dementia. Apathy refers to a disorder of behavioral initiation or intention that can manifest in different ways like retarded emotional expression but not depression, and the failure to initiate a range of behaviors related to activities of daily living (ADL), that can be performed but are not initiated by the patient (Marin, 1991a). Although, there is some overlap with depressive symptoms, several groups have established apathy as a distinct entity lacking symptoms of dysphoria, suicidal ideation, self-criticism, feelings of guilt, and hopelessness (Levy et al., 1998). The prevalence of apathy in MCI has been reported to be as high as 60.5% (Ellison et al., 2008, Hwang et al., 2004, Lyketsos et al., 2002, van der Linde et al., 2016). Apathy appears early during MCI, increases in severity as the disease progresses, and tends to have a chronic course. In a population based study of older adults followed over ten years (N=3626), apathy was noted to be highly prevalent at 31.9%; and symptoms persisted for at least one year in 62% of subjects with apathy (van der Linde et al., 2016). Furthermore, the mortality rate among those with apathy was 3.1 times higher compared to those without apathy (van der Linde et al., 2016). Presence of apathy leads to rapid progression of symptoms and up to seven-fold rate of conversion to AD (Palmer et al., 2010). Thus, treatment of apathy in MCI has the potential to influence the trajectory of neurodegeneration.
Pharmacological treatment options for apathy are limited and may not be tolerated by many patients. Medications currently approved for AD have had mixed results in treating apathy; while cholinesterase inhibitors were effective in improving apathy in secondary analyses, memantine failed to do so (Cummings et al., 2005, Zhang et al., 2015). Modest improvements in apathy and cognitive correlates have been noted with dopaminergic agents such as methylphenidate (Padala et al., 2017, Herrmann et al., 2008, Padala et al., 2010, Rosenberg et al., 2013). Our group has found that the best outcomes of apathy with methylphenidate were after 12 weeks of treatment and some domains of apathy such as novelty seeking and persistence still did not respond (Padala et al., in press). Furthermore, stimulants may not be suitable for those with polypharmacy, and cardiac abnormalities. A recent review of available pharmacological treatments for apathy concluded that they have limited effectiveness, are expensive, and sometimes induce prohibitive side effects (Rea et al., 2014). Therefore, alternative or complementary adjuvant therapeutic strategies need to be explored. Repetitive Transcranial Magnetic Stimulation (rTMS), a noninvasive brain stimulation tool, is a potential therapeutic tool for apathy in MCI that might lead to rapid improvement in apathy and in signs and symptoms seemingly unresponsive to pharmacological treatments. Thus, the primary objective of our study was to establish the feasibility and efficacy of repetitive transcranial magnetic stimulation (rTMS) to improve apathy in older adults with MCI.
Section snippets
Study design and participation
This pilot study was a single site, double blind, randomized, sham-controlled, cross-over study of daily rTMS treatments five-times per week (20 sessions) with 4-weeks of treatment-free period between the interventions. The study was conducted at a Department of Veterans Affairs Medical Center. The protocol was approved by the Institutional Review Board of the Central Arkansas Veterans Healthcare System. Subjects were recruited via advertisements in clinical areas and referral from providers.
Results
The screening, enrollment, and participation process is depicted in Fig. 1. A total of 79 patients were screened to randomize nine subjects. Mean (SD) age of the subjects was 65.6 (9.3) years, four were Caucasian and five African American, and one subject was female. Four subjects were randomized to receive the active-coil treatment first, and five subjects to receive the sham-coil treatment first. One subject randomized to the active-coil treatment was withdrawn after the baseline visit, as he
Discussion
The main objective of the study was to compare the effects of rTMS to sham treatment on apathy in those with MCI. There was a significantly greater improvement in apathy scores after 10 rTMS treatment sessions compared to an equal number of sham treatments. Enhanced dopamine transmission in the prefrontal cortex, the ipsilateral anterior cingulate, and medial orbitofrontal cortex with left DLPFC high frequency rTMS, as detected in prior studies, could explain the improvement in apathy seen in
Acknowledgments
We would like to thank all the subjects and their caregivers.
Conflict of interest
There are no financial conflicts of interest or personal conflict of interest relevant to the submitted manuscript for any authors.
Sponsor's role
This study (ClinicalTrials.gov Identifier: NCT02190019) was supported by award number 1UL1RR029884 from the National Institutes of Health (PRP), SCVAHCN Network Research Grant Program by Department of Veterans Affairs (PRP), MIRECC VISN 16 Pilot grant (PRP), Neuronetics Inc. Investigator Initiated Trial award (supplies only) (PI: Prasad Padala, MD). The sponsors had
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