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 Table of Contents  
REVIEW
Year : 2022  |  Volume : 1  |  Issue : 4  |  Page : 148-154

Potential application of repetitive transcranial magnetic stimulation for apathy after traumatic brain injury: a narrative review


1 Division of Physical Medicine and Rehabilitation, Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
2 Department of Neurology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

Date of Submission05-Dec-2022
Date of Decision09-Dec-2022
Date of Acceptance20-Dec-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Bei Zhang
Division of Physical Medicine and Rehabilitation, Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2773-2398.365024

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  Abstract 


Apathy is a common sequela to traumatic brain injury affecting multiple aspects of the patient’s rehabilitation, recovery, domestic and social functioning, and quality of life. As a motivational disorder, it is distinct from depression, but shares many similar features. Anatomically, they both involve dysfunction in the ventral and medial prefrontal cortices and the anterior cingulate cortex; however, the dorsal anterior cingulate cortex may be more implicated in regulating motivation, while the subgenual anterior cingulate cortex may be more involved in regulating mood. Current treatment for apathy is limited, especially when standard pharmacotherapies for depression have not been shown to improve apathy. Repetitive transcranial magnetic stimulation is a neuromodulatory therapy effective for refractory depression. The mood modulatory effect was believed related to the anti-correlation between the subgenual anterior cingulate cortex and left dorsolateral prefrontal cortex. Studies have recently shown its safety and successful treatment of apathy in Parkinson’s disease, Alzheimer’s disease, and stroke, although the mechanism has not been fully elucidated. Repetitive transcranial magnetic stimulation has also been successfully applied in persons with traumatic brain injury for depression, dizziness, central pain, visual neglect, cognitive impairments, and disorders of consciousness. In this review, we aimed to summarize the current understanding of apathy and evidence of the clinical application of repetitive transcranial magnetic stimulation to explore the theoretical basis of potential therapeutic benefits of using repetitive transcranial magnetic stimulation for apathy after traumatic brain injury.

Keywords: apathy; cingulate cortex; prefrontal cortex; transcranial magnetic stimulation; traumatic brain injury


How to cite this article:
Ashcraft T, Breazeale L, Kahathuduwa C, Zhang B. Potential application of repetitive transcranial magnetic stimulation for apathy after traumatic brain injury: a narrative review. Brain Netw Modulation 2022;1:148-54

How to cite this URL:
Ashcraft T, Breazeale L, Kahathuduwa C, Zhang B. Potential application of repetitive transcranial magnetic stimulation for apathy after traumatic brain injury: a narrative review. Brain Netw Modulation [serial online] 2022 [cited 2023 Jan 28];1:148-54. Available from: http://www.bnmjournal.com/text.asp?2022/1/4/148/365024




  Introduction Top


Each year, there are about 2.5 million traumatic brain injury (TBI)-related emergency department visits and 250,000 TBI-related hospitalizations in the USA (Centers for Disease Control and Prevention and National Center for Injury Prevention and Control, 2022). Apathy is one of the most common sequelae of TBI and can markedly impact recovery, independence, social reintegration, and quality of life (Worthington and Wood, 2018; Palmisano et al., 2020). Reportedly, its prevalence ranges from 16% to 71%, depending on the definition, assessment tools, and reporting sources (Worthington and Wood, 2018). Traditionally, apathy has been evaluated as part of depression, although this has been challenged (Kirsch-Darrow et al., 2011; Njomboro and Deb, 2012). Studies have shown that apathy more commonly contributes to impaired self-awareness and difficulties in activities of daily living than depression after TBI (Bivona et al., 2019; Green et al., 2022; Ubukata et al., 2022). It is of critical importance to identify the primary drivers that affect patients’ recovery and functioning to develop targeted therapies. Therefore, we attempted to summarize the current understanding of apathy and evidence of the clinical application of repetitive transcranial magnetic stimulation (rTMS) to explore the theoretical basis of potential therapeutic benefits of using rTMS for apathy after TBI.

Apathy

Motivation is understood as the direction, intensity, and persistence of one’s actions (Marin, 1991). Apathy, originating from the Greek word “pathos”, describes a decrease in or loss of motivation, causing decreases in self-generated, goal-directed behaviors, impairments in cognition, alterations in mood, and dysfunctions in daily activities (Robert et al., 2018). The syndrome of apathy is considered unique and is not attributed to disturbances in intellect (e.g., dementia), emotion (e.g., depression), consciousness (e.g., drowsiness), or the influence of drugs. However, apathy can present as a symptom in various diseases, such as stroke, neurocognitive disorders, Parkinson’s disease (PD), major depressive disorder (MDD), and schizophrenia (Marin, 1991; Husain and Roiser, 2018; Miller et al., 2021). Apathy belongs to disorders of diminished motivation, which represents a spectrum of lack of motivation in behaviors, cognition, and emotion (Palmisano et al., 2020). Apathy falls on the milder end, presenting as decreased motivation in behaviors compared with one’s baseline, with impaired initiation and reduced activity and concerns (Lane-Brown and Tate, 2009). Abulia is a more severe form, presenting as reduced spontaneous and purposeful movements (Lane-Brown and Tate, 2009). The most disabling condition in disorders of diminished motivation is akinetic mutism, with which the person is awake and appears alert but has no voluntary movements or speech output due to the absence of drive for personal needs (Palmisano et al., 2020).

The similarities in the clinical presentation of apathy and depression sometimes make them difficult to differentiate. While they share certain manifestations [Figure 1], such as loss of interest/pleasure (i.e., anhedonia) and low energy, the manifestation of MDD is centered on depressed mood, or sadness/negativity (Kirsch-Darrow et al., 2011). In comparison, apathetic presentations consist of a reduced drive in expressing emotions or reduced emotional reactions, resulting in a flat effect (Lane-Brown and Tate, 2009; da Costa et al., 2013). A brief comparison of the diagnostic criteria for apathy and MDD is summarized in [Table 1]. Studies have suggested that apathy and depression have discrete constructs and could be differentiated based on item clusters using Beck Depression Inventory-II after TBI (Kirsch-Darrow et al., 2011; Ubukata et al., 2022).
Figure 1: Similarities and differences in symptom profiles and neuroanatomical substrates of apathy, depression, and alexithymia (Ready et al., 2016; Fahed and Steffens, 2021).
Note: DLPFC: Dorsolateral prefrontal cortex; DACC: dorsal anterior cingulate cortex; VMPFC: ventromedial prefrontal cortex; VTA: ventral tegmental area.


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Table 1: Comparison of the diagnostic criteria for apathy and major depressive disorder

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Another cognitive-affective disorder that may further complicate the clinical picture after TBI is alexithymia. It is characterized by impairment in the ability to elaborate on one’s feelings (Ready et al., 2016). The estimated incidence is about 15% in persons with acquired brain injury, among which patients with TBI had greater levels of overall alexithymia compared with non-TBI patients (e.g., stroke and brain tumor) (Fynn et al., 2021). In TBI, the number varies from 5% to 77% with a median of 21% (Fynn et al., 2021). The understanding of alexithymia after TBI remains limited. Studies have shown that alexithymia was inversely related to emotional empathy (the ability to vicariously experience the emotions of others) (Williams and Wood, 2010), quality of life (Henry et al., 2006), and quality and satisfaction of relationship (Williams and Wood, 2013), while markedly associated with aggressive tendencies (Williams et al., 2018) and suicidal ideation (Wood et al., 2010). In a previous study, the only overlapping feature between apathy and alexithymia appeared to be difficulty in describing feelings (Ready et al., 2016). The most distinguishing features of alexithymia included confusion about bodily sensations and difficulty in opening up to others (Ready et al., 2016). Impaired facial emotion recognition may occur in both apathy and alexithymia (Ready et al., 2016). Despite overlapping manifestations, these syndromes could occur independently or concurrently as symptoms in various neurological diseases (Ready et al., 2016).

Neural structures supporting normal motivated behaviors are primarily located in the ventromedial prefrontal cortex (vmPFC), medial orbitofrontal cortex, dorsal anterior cingulate cortex (dACC), and ventral striatum (vStr) (Le Heron et al., 2018; Gracia-García et al., 2021). The dACC-vStr circuit is the most consistently identified structure, with other areas implicated less consistently (Le Heron et al., 2018; Fahed and Steffens, 2021). The circuit may be involved in five major processes generating motivative behaviors, which include willingness to initiate an action, weigh cost-benefit of different actions, anticipate and prepare actions, initiate and sustain performance, and learn whether actions are worth performing (Husain and Roiser, 2018; Fahed and Steffens, 2021). The value ascribed to performing an action (i.e., reward anticipation) is considered distinct from the hedonia (i.e., pleasure) experienced in response to rewarding outcomes (Fahed and Steffens, 2021). Anhedonia is linked to activity in the medial orbitofrontal cortex and vStr. The pathophysiology of MDD shares these neuroanatomical substrates. Reduced activation was observed in vmPFC, medial orbitofrontal cortex, vStr, dACC (although inconsistent), and caudate (Husain and Roiser, 2018). Deep brain stimulation of subgenual anterior cingulate cortex (sgACC, part of ventral anterior cingulate cortex) improved depressive mood that was resistant to other treatments (Mayberg et al., 2005), but the treatment effect was inconsistent (Holtzheimer et al., 2017). Deep brain stimulation of anterior mid-cingulate cortex [part of dorsal anterior cingulate cortex (dACC)] was able to induce the feeling of determination to overcome an imminent challenge (Parvizi et al., 2013). Neuromodulation attempted over these areas demonstrated the underlying neuroanatomical construct associated with the syndromes. Few studies were focused on the anatomical basis of apathy after TBI (Worthington and Wood, 2018). Limited evidence suggests apathy after TBI may result from injuries to prefrontal cortex, anterior cingulate cortex, amygdala, striatum, insular cortex, as well as white matter tracts that constitute cortico-subcortical circuits connecting the previously mentioned regions (Worthington and Wood, 2018; Palmisano et al., 2020). The finding is largely consistent with what was reported in other neurologic and psychiatric diseases. Hogeveen et al. (2021) found that increased apathy scores in TBI were associated with decreased vmPFC-dACC functional connectivity as measured using resting state functional magnetic resonance imaging. Their results also showed vmPFC-dACC hyperconnectivity may be an adaptive compensatory response, building resilience to apathy after TBI (Hogeveen et al., 2021).

Currently, there is no standard therapy for apathy. Previous studies suggested the first-line treatment for depression, selective serotonin receptor inhibitors, may worsen or even lead to the development of apathy (Zahodne et al., 2012; Padala et al., 2020). Cholinesterase inhibitors have been used to treat apathy in Alzheimer’s disease (AD) with no or limited beneficial effects (Rea et al., 2014; Nobis and Husain, 2018), although donepezil combined with cholinergic precursor choline alphoscerate showed some promising results (Rea et al., 2015). Overall, agents that modulate dopaminergic and noradrenergic tone showed the greatest potential in pharmacological treatment for apathy (Pérez-Pérez et al., 2015; Padala et al., 2018a; Cools et al., 2019; Palmisano et al., 2020; Fahed and Steffens, 2021; Hezemans et al., 2022); however, convincing evidence is still needed (Andrade, 2022). Methylphenidate was studied in mild AD and was found to improve apathy over 12 weeks (Padala et al., 2018a). Pramipexole was found to lower total apathy scores markedly when compared with ropinirole and L-dopa in PD (Pérez-Pérez et al., 2015). Atomoxetine was found effective in the performance of patients with PD in an effort-based visuomotor task when stratified based on locus coeruleus integrity (Hezemans et al., 2022). The evidence shed light on potential pharmacological options for apathy in TBI. As the development of treatments for apathy is still in its infancy, non-pharmacological therapies, such as motivation-based behavior therapy, cognitive therapy, music therapy, animal therapy, and multi-sensory stimulation, have also shown effectiveness and should be incorporated (Worthington and Wood, 2018; Manera et al., 2020; Palmisano et al., 2020). In recent years, neuromodulation techniques advance rapidly. Neuromodulation has gained increased attention and popularity in the treatment of neuropsychiatric conditions. Among the available modalities, transcranial magnetic stimulation (TMS), a non-invasive approach of neuromodulation, has proved its efficacy in treating refractory depression and has been trialed in treating apathy in various diseases.


  Transcranial Magnetic Stimulation and Its Clinical Application for Apathy Top


TMS induces neural activity through rapidly alternating magnetic fields across the skull (Pink et al., 2021). By delivering a pulsatile series of the magnetic field, rTMS is versatile and can induce excitatory or inhibitory cortical activities depending on location and frequency (Pink et al., 2021). Since its development, TMS has generally been considered painless, effective, and safe in treating many conditions. The technology was approved by the U.S. Food and Drug Administration (FDA) in 2008 for treatment-resistant MDD in adults (Cohen et al., 2022). Over the past decade, the TMS field has grown substantially. Devices containing advanced cortical mapping algorithms and different stimulation protocols have been developed by several companies and obtained FDA approval for clinical application (Cohen et al., 2022). The technology further expands its clinical indication, approved by the FDA, to migraine headache with aura (in 2013), obsessive-compulsive disorder (in 2017), smoking cessation (in 2020), and anxiety comorbid with depression (in 2021) (Cohen et al., 2022). TMS can now be personalized based on an individual’s cortical anatomy and can deliver the stimulation by pinpointing the targeted location within 2 mm (Cash et al., 2021). The mechanism of making individualized antidepressant therapy is even more interesting. Three studies consistently showed the degree of negative functional connectivity (anticorrelation) between the dorsolateral prefrontal cortex (DLPFC) and sgACC was able to predict the antidepressant effect of rTMS (Fox et al., 2012; Weigand et al., 2018; Cash et al., 2019), revealing specific neuromodulatory influence on cortical structures and the resultant clinical effect. TMS is a promising non-invasive neuromodulation modality. With ongoing efforts in enhancing its technology and exploring new indications, TMS is expected to have wide utility in treating neuropsychiatric conditions.

In recent years, TMS has been used to treat apathy in various neurological disorders and has shown favorable outcomes. Padala et al. (2018b) applied 10 Hz rTMS to the left DLPFC in a small series of patients with mild cognitive impairments. They found a marked decrease in apathy, evaluated by the Apathy Evaluation Scale, after real stimulation. In addition, improvements were found in several secondary outcomes, such as cognitive and executive functions (Padala et al., 2018b). Subsequently, a double-blind randomized controlled pilot study was conducted on patients with AD. They found patients receiving 10 Hz rTMS had significant improvements in apathy, evaluated by the Apathy Evaluation Scale, compared with sham treatment; also in cognition and daily functioning (Padala et al., 2020). Nguyen et al. (2017) performed a pilot study using multi-site rTMS combined with cognitive treatment (rTMS-COG) in AD. 10 Hz rTMS was applied to six brain regions, including left and right DLPFC, left and right parietal cortices, left inferior frontal gyrus (Broca’s area) and left superior temporal gyrus (Wernicke’s area). In this study, rTMS-COG therapy significantly improved apathy, evaluated by the Apathy Inventory, as one of the secondary endpoints, along with improved cognition and independence at the end of the treatment and 6-month follow-up (Nguyen et al., 2017). Another retrospective study focused on the long-term effects of rTMS-COG in AD. They found marked improvements in apathy, evaluated by the Apathy Inventory, at 3-month and 1-year follow-ups; and this was maintained at 4-year follow-ups (Suarez Moreno et al., 2022). So far, rTMS over left DLPFC and rTMS-COG are considered to be effective in treating apathy in AD patients, especially at an early stage (Di Lazzaro et al., 2021). TMS has also been shown to be effective in reducing apathy levels in patients with chronic stroke using 10 Hz rTMS over the region spanning from the dACC to mPFC (Sasaki et al., 2017) and in patients with PD using 5 Hz rTMS over the supplementary motor area (Oguro et al., 2014).


  Potential Application of Repetitive Transcranial Magnetic Stimulation for Apathy after Traumatic Brain Injury Top


The aforementioned studies have demonstrated the promising utility of rTMS in the treatment of apathy. As mentioned above, apathy is common after TBI and can exert detrimental consequences on a patient’s recovery, functionality, and quality of life. A single symptom can cut across many neuropsychiatric disorders that may share pathologies in similar underlying neural substrates (Cuthbert, 2015). Therefore, based on the current understanding of neuroanatomical correlations and the clinical application of rTMS, it may help alleviate apathetic symptoms after TBI. However, such evidence is lacking.

There is an increased interest in and call for using non-invasive neuromodulation in neurorehabilitation after TBI, especially TMS (Pape et al., 2006; Bender Pape et al., 2020). TMS has been safely applied to a wide spectrum of the TBI population, the evidence of which is robust (Hoy et al., 2019; Anderson et al., 2020; Oberman et al., 2020; Pink et al., 2021; Li et al., 2022). However, when considering applying rTMS to patients with TBI, the seizure has been one of the major concerns (Pink et al., 2021). Stultz et al. (2020) looked at TMS-related seizures with various coils, protocols, and other factors and concluded the overall TMS-related seizure risk is < 1%. It is believed that the incidence of TMS-related seizures is comparable to that of most psychotropic medications (Stultz et al., 2020). Additionally, single pulse rTMS has been routinely used to map language areas in patients with brain tumors and secondary epilepsy without eliciting seizure activities (Tarapore et al., 2016). Despite the uncommon occurrence of TMS-related seizures, attempts were made to ensure patients’ safety (Pink et al., 2021). Studies (Louise-Bender Pape et al., 2009; Pink et al., 2021) developed comprehensive data safety monitoring plans for using rTMS in a patient with severe TBI, including daily medical examination before rTMS, electroencephalogram conducted before and after rTMS, seizure response plan, and oversight by a data safety monitoring board. This rigorous safety protocol caught a subclinical seizure following rTMS in another TBI patient and an adapted rTMS regimen was subsequently implemented without further adverse events (Pape et al., 2014; Pink et al., 2021).

Overall, rTMS was found effective in depression, dizziness, central pain, and visual neglect after TBI, while less encouraging in mixed cognitive impairments and prolonged disorders of consciousness (Pink et al., 2021). rTMS was found well tolerated in post-TBI depression, although its therapeutic benefit remains inconclusive (Hoy et al., 2019; Anderson et al., 2020). A marked short-term antidepressant effect (Cohen’s ᵟ = 1.03 [95% confidence interval 0.20, 1.86]) of DLPFC rTMS in patients with TBI was revealed in a recent meta-analysis, the effect of which reportedly dissipated at 1-month follow-up (Tsai et al., 2021). rTMS was shown effective in improving working memory and executive function, which is related to prefrontal lobe functions (Hoy et al., 2019). While Tsai et al. (2019) did not observe marked improvements in processing speed and selective attention among patients with TBI following rTMS, a statistically significant, yet subtle improvement in visuospatial memory was observed (Cohen’s ᵟ = 0.39 [95% confidence interval 0.21, 0.56]). However, the overall therapeutic benefits of rTMS on cognitive impairments after TBI remain inconclusive (Neville et al., 2019; Anderson et al., 2020). Additionally, one study showed high-frequency rTMS did not help ameliorate anxiety symptoms following moderate to severe TBI (Rodrigues et al., 2020). Several studies showed that rTMS improved headache, overall pain, and quality of life in patients with TBI, which is also promising but inconsistent at this time (Anderson et al., 2020). Most studies were heterogenous regarding TBI severity, symptom domains, assessments, and rTMS protocols, making the synthesis of the results and further interpretation difficult. Specifically, barriers related to the application of rTMS for apathy may include limited understanding of the best anatomical stimulation location (e.g., right vs. left DLPFC or other brain regions), best rTMS dosing (e.g., frequency, duration, session, cumulative exposure), and sustainability of the effects of different rTMS protocols. Also, the inherent demographic characteristics of TBI and certain post-TBI comorbidities may affect the treatment effects of rTMS. These factors need to be considered when designing the study protocols and further investigated in adequately powered studies.


  Conclusion Top


Apathy has a relatively high incidence rate after TBI. It can affect a patient’s rehabilitation, recovery, domestic and social functioning, and quality of life. Apathy is a motivational disorder, presenting as a decrease in or loss of motivation, which is distinct from depression. Nevertheless, they share certain symptom profiles. They both involve dysfunction in ventral and medial prefrontal cortices and anterior cingulate cortex; however, dACC may be more implicated in regulating motivation, while sgACC in regulating mood. It appears that the development of apathy is associated with decreased functional connectivity between vmPFC and dACC. rTMS over left DLPFC is an established therapy for refractory depression. The antidepressant effect can be predicted and individualized based on anti-correlation between sgACC and the stimulation site at the left DLPFC, indicating a modulatory effect from DLPFC to sgACC. Incorporating current evidence, rTMS has been applied to left DLPFC, multi-site, supplementary motor area, and regions spanning from dACC to mPFC in treating apathy resulting from AD, PD, and chronic stroke. It is possible that certain areas of the PFC (for example, left or right DLPFC, or mPFC) could exert modulatory effects on dACC, thus modulating motivational drive and ameliorating apathy. TMS has been safely applied to persons with TBI. Hypothetically, such therapy might be beneficial and applicable to apathy after TBI. The review is limited by its narrative nature and could only provide a theoretical basis for such clinical application. Well-designed studies are warranted.

Author contributions

Conceptualization and project administration: BZ; literature search and review, writing—original draft preparation: TA, BZ; writing—review and editing: LB, CK, TA, BZ. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

None.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.[66]



 
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