Music and Memory in Alzheimer’s Disease and The Potential Underlying Mechanisms

Abstract

With population aging and a projected exponential expansion of persons diagnosed with Alzheimer’s disease (AD), the development of treatment and prevention programs has become a fervent area of research and discovery. A growing body of evidence suggests that music exposure can enhance memory and emotional function in persons with AD. However, there is a paucity of research that aims to identify specific underlying neural mechanisms associated with music’s beneficial effects in this particular population. As such, this paper reviews existing anecdotal and empirical evidence related to the enhancing effects of music exposure on cognitive function and further provides a discussion on the potential underlying mechanisms that may explain music’s beneficial effect. Specifically, this paper will outline the potential role of the dopaminergic system, the autonomic nervous system, and the default network in explaining how music may enhance memory function in persons with AD.

Keywords

Alzheimer’s disease autobiographical memory default network dopamine mechanisms music sympathetic activity

With population aging and a projected increase in persons who will be diagnosed with dementia, cognitive impairment has emerged as one of the leading health concerns among older adults. According to the World Health Organization [1], approximately 36 million people are living with dementia, which is expected to double by 2030 and triple by 2050. Consequently, the development of low-cost, accessible interventions that promote cognitive function and maintain quality of life in persons diagnosed with dementia is imperative.

Music perception involves the integration of various complex dynamic elements including, but not limited to pitch, timbre, and rhythm. In addition to sensory processing, music is found to significantly impact emotional processing [2] and the encoding and recall of memories [3]. Recent research indicates that music can enhance learning of associated verbal information in persons with Alzheimer’s disease (AD) [4], the most common form of dementia.

Evidence supporting the beneficial effects of music on cognitive and behavioral functions in persons with AD has been previously reviewed [5 –10]. However, the specific potential underlying mechanisms which could help to explain the “how” and “why” behind memory-enhancing effects of music have not been examined and remain unclear. In this review, we examine current anecdotal and empirical evidence supporting music as an effective way to aid in the acquisition of new information and memory in persons with AD. Further, we explore potential underlying mechanisms that may explain how music exerts its effect. Before delving into the effectiveness of music as a memory enhancer, a brief overview of the pathophysiology of AD is requisite.

NEURONAL AND SYMPTOM CHARACTERISTICS OF ALZHEIMER’S DISEASE

Deterioration of central nervous system integrity among person with AD arises from chronic dysfunction of various neurochemical messenger systems. Over three decades of research has elucidated the role of cholinergic dysfunction in AD pathology and progression, including the development of abnormal amyloid-β protein precursor processing and phosphorylation of tau protein, resulting in the well-characterized amyloid plaques and neurofibrillary tangles of the AD brain [11, 12]. Significant structural abnormalities begin with neuropathological changes in regions of the medial temporal lobe (MTL), namely the entorhinal cortex [13]. Disruption in entorhinal cortex function compromises communication between the hippocampus of the MTL and the prefrontal cortex (PFC), and further results in observable functional and structural changes in these brain regions [14]. While the vast majority of research focuses on atrophy of the hippocampus, recent evidence also points to regions of the limbic system, including the amygdala, ventral striatum, and insular cortex. The amygdala is a MTL structure that is important for emotional processing and responsivity, which is reportedly compromised in very mild stages of AD [15]. The amygdala communicates with other MTL structures and structures of the PFC, which may mediate the effect of emotional arousal on declarative memory [16]. Atrophy of the amygdala in patients with early stage AD is a unique predictor of declarative memory performance, beyond associations to hippocampal atrophy [17]. The ventral striatum, which is important for motivation and processing of reward [18, 19], is also found to be compromised in patients with AD, evidenced by significant decreases in cholinergic neurons [20]. Finally, atrophy of the insular cortex, which projects to the amygdala and ventral striatum, is displayed in patients with AD [21], resulting in deficits in attention, perceptual decision-making, emotional awareness, cognitive control, and performance monitoring [22].

Progressive cortical atrophy in AD corresponds to significant progressive deterioration in episodic and semantic memory, followed by declines in executive, attentional, perceptual, and visual-spatial abilities [23]. Of particular note is the impairment in autobiographical memory among patients with AD [24, 25]. Autobiographical memory consists of personal semantic and episodic memory components, both of which contribute to a sense of individual identity. Although semantic autobiographical memory, which is generalized or fact-based, remains relatively intact in early stages of AD; episodic memory, which is contextually rich in relation to time and place of an event, is typically compromised in very early stages of AD [25]. Declines in autobiographical memory recall is associated with feelings of detachment and progressive feelings of lost identity, including the material-self, social-self and spiritual-self, which further correlates with increased apathy [26]. Additional clinical symptom presentation may include depression, anxiety, agitation and psychosis [27].

MUSIC PERCEPTION AND THE BRAIN

Music is a powerful agent that can alter skin conductance, respiration patterns, blood pressure, heart rate, and subjective emotional responsivity [28]. Research suggests that emotional and physiological responses to music are mediated by limbic structures that subsequently communicate with larger cortical networks [29].

Music has been shown to activate brain regions associated with emotion, reward, and decision-making. Studies report enhanced activation in the ventral medial prefrontal cortex (VMPFC) and the orbitofrontal cortex while listening to music that is considered to be emotionally moving [30, 31]. Both frontal structures, which can be compromised in persons with AD [32], are implicated in emotion regulation and decision making; the orbitofrontal cortex is implicated in emotion and reward during decision making [33] whereas the VMPFC is implicated in the processing of fear and emotional inhibition [34]. Together, these frontal cortices are considered to be critical for integration of emotion and sensory information through reciprocal connections with subcortical limbic structures including the amygdala [35]. In a study by Blood and Zatorre [36], musicians who reported experiencing chills while listening to music displayed an increase from baseline in cerebral blood flow to the VMPFC, the orbitofrontal cortex, the amygdala, and the ventral striatum. Research further shows that the hippocampus and inferior frontal gyrus are activated when retrieving musical information [37]. Importantly, these structures are compromised in person with AD.

In assessing neuronal activation in response to valence of musical composition, research has demonstrated the complexity of music processing. Using functional magnetic resonance imaging (fMRI), Koelsch and colleagues [2] revealed differential activation patterns as a function of music valence. Specifically, listening to pleasant music appears to associate with significant activation of the ventral striatum and anterior insula, relative to unpleasant music; whereas unpleasant music elicits greater activation in the amygdala, hippocampus, and temporal poles, relative to pleasant music [2]. Based on these findings, the authors posit that music may have the ability to up- and down-regulate activity in limbic and paralimbic structures [2]. We further postulate that the ability of music to regulate activation of brain regions that are compromised in AD may hold important implications for ameliorating cognitive dysfunction in the AD population.

MUSIC AS A MEMORY ENHANCER IN ALZHEIMER’S DISEASE

In the last decade, researchers have explored the role of music as a memory enhancer in persons with AD. While initial case reports have provided anecdotal evidence, recent empirical studies provide preliminary evidence for the ability of music to modulate memory function in persons with AD.

Music as a memory enhancer: Case studies

The first published case study that explored the role of music in memory function was the case of “ML”, a professional pianist diagnosed with severe dementia [38]. While ML was able to play familiar music, the patient was unable to learn new songs. ML’s case aligned with the common idea that patients with AD cannot learn new information based on impaired short-term memory [39]. A more recent case study, however, suggests that individuals with dementia of the AD type can learn and remember new information in the form of music. Cowles and colleagues [40] described the case of patient “SL”, a violinist who displayed moderate symptoms of dementia and was diagnosed with probable AD. Despite marked deficits in recall and recognition on a variety of standardized memory tasks, SL was able to learn how to play new music on her violin. In assessing the association between music and memory, Cuddy and Duffin [41] report the case of “EN” who was diagnosed with probable AD and displayed severe memory and cognitive impairments. Although unable to respond and sing along with unfamiliar new melodies, EN was able to respond to familiar melodies and familiar melodies that were digitally distorted [41]. Although this was a single case study, EN’s ability to recognize and sing along with familiar digitally distorted melodies suggests that musical memory can be spared to some degree in AD.

Anecdotal reports have lead researchers to examine whether music perception and production may provide the pathological aging brain with resources necessary to support cognitive abilities in persons with AD.

Music as a memory enhancer: Current empirical support

Studies in non-demented older adults suggest that listening to music may enhance autobiographical memories, which are considerably impaired in persons with AD.

An early study in healthy older adults by Schulkind and colleagues [42] showed that listening to music excerpts from one’s adolescence resulted in the evocation of autobiographical memories characterized by increased specificity and emotionality, relative to memories recalled when listening to music from a later life period. It may be postulated that music plays a role in constructing autobiographical memories throughout the lifespan, attaching strong personal and emotional meaning to these particular memories, which may allow music to facilitate access to memories for specific life events, enabling a sense of identity and remembrance, which is significantly diminished in persons with AD [26].

Music has shown to facilitate autobiographical memories in persons with AD. In investigating the effect of background music versus a silent testing condition on autobiographical memory in persons with mild AD, Irish and colleagues [43] found that total autobiographical recall was significantly better in the music relative to the silent condition. To determine whether observed benefits in autobiographical memory in patients with AD are music-specific, Meilán García and colleagues [44] played excerpts from different pieces of music, including happy music, sad music, new music (i.e., drum-line cadence), and industrial noise (i.e., cafeteria sounds). Results showed that autobiographical memory was significantly better when exposed to sad music compared with all other conditions, but only for recall of remote memories and not for recent memories. Thus, it appears that music is able to enhance long-term episodic recall of events. The authors suggest that it is not the music per se, but the emotion that accompanies the music that enhances remote autobiographical memory recall and further suggest that the ability of music to particularly stimulate recall of remote rather than recent autobiographical memories may be important in regaining a sense of identity. More recently, El-Haj and colleagues [45] showed that music-evoked autobiographical memories (MEAMs) are more characteristic of involuntary memories, defined as memories that are more emotionally laden, are recalled more spontaneously and are triggered without conscious awareness by an environmental cue. Research evaluating MEAMS have shown that selection of music, that is, self-selected music versus experimenter-selected music, significantly determines the effectiveness of music in enhancing autobiographical memories. Not only has self-selected music been found to increase the frequency of emotional words used to recall events [46], but has further been shown to improve grammatical complexity in persons with mild AD [47]. Notably, the differential effect of self-selected, versus researcher-selected, music is limited to persons with AD and does not extend to non-demented older adults [6 –10].

Given that MEANs are enhanced by music rated high in familiarity and emotion [48 –50], it is suggested that familiar music is associated with sense of identity. Arroyo-Anlló and colleagues [51] examined the impact of familiar music on domains of self-consciousness in patients with AD over a 3-month period, relative to an age-matched control group exposed to unfamiliar music. Results indicated that a slight benefit in self-consciousness was reported following the duration of the familiar music intervention relative to baseline, however this did not reach statistical significance. Notably, the experimental group showed enhanced feelings of self-consciousness in the domains of personal identity and affective state, whereas the control group did not show any improvement or stabilization of self-consciousness [51].

In addition to enhancing autobiographical memory and sense of self, research suggests that music presented at encoding may enhance subsequent memory recognition of new verbal information in persons with AD. Simmons-Stern and colleagues [4] examined the effects of music on recognition of novel verbal material that was either spoken or sung at encoding. Participants with probable AD and age-matched healthy controls were presented with unfamiliar song lyrics that were either spoken or sung. Although healthy older adults outperformed participants with AD, results showed that the AD group displayed better recognition accuracy of lyrics when the lyrics were sung rather than spoken at encoding [4]. Although healthy controls did not benefit from singing the lyrics at encoding, it is possible that the recognition task was too simple for healthy older adults, causing a ceiling effect. To increase difficulty of the memory task, a follow-up study [52] investigated recognition of content-specific information (i.e., deeper context-specific) and general content information (i.e., general familiarity) of lyrics presented when sung or spoken at encoding. Results showed that singing was an effective mnemonic strategy to enhance recognition for general content in both patients with AD and healthy controls. However, neither group displayed this effect for content-specific items, suggesting that music may help encode and retrieve surface level information, but does not enhance encoding and retrieval of deeper-level information.

Thus, research appears to suggest that music may enhance or facilitate certain aspects of episodic memory, which progressively deteriorates in persons with AD, including remote autobiographical memory and episodic memory for recently learned lyrics. As musical processing and memory for music is relatively preserved in AD patients [49, 53], the experience of music can create a sense of enjoyment for the patient even as the disease progresses. Further, research demonstrates that music is a highly effective stimulus capable of eliciting autobiographical memories and enhancing associated emotions, something which is crucial to a feeling of identity and optimal well-being, which deteriorates with the progression of AD. Despite growing empirical findings, there is a paucity of research that has assessed mechanisms underlying the memory-enhancing effect of music. The remaining portion of this review will discuss probable pathways in which music can enhance memory in persons with dementia.

POTENTIAL MECHANISMS UNDERLYING MUSIC AS A MEMORY ENHANCER

Three independent, yet interconnected, mechanisms can be hypothesized to underlie the beneficial effect that music plays in enhancing memory in persons with AD. These mechanisms include the activation of dopaminergic pathways, sympathetic arousal, and default neuronal connectivity.

Music and dopaminergic pathways

The dopaminergic system plays an important role in behavior and in the regulation of cognition. Dopamine is a neurotransmitter that is integral to processes of reward and motivation, and interacts with acetylcholine to facilitate learning and memory consolidation of newly acquired information, evidenced at both the behavioral and cellular level (for review see [54]). The dopaminergic cell bodies are located in the ventral tegmental area (VTA), which is the starting point of two dopaminergic pathways, the mesolimbic and mesocortical pathways [55]. The mesolimbic pathway includes dopaminergic projections from the VTA to the nucleus accumbens (NAc), and plays a critical role in the reward system by processing the anticipation and salience of rewarding stimuli in both pleasant and aversive situations, further creating motivation for stimulus acquisition [31 , 57]. Notably, the VTA also projects to other cortical areas such as the PFC, amygdala, and the hippocampus [58], all of which are involved in learning and memory consolidation.

Dopaminergic pathways that project from the VTA to the NAc and MTL are notably compromised in AD [59]. Not only has dopaminergic depletion been documented in persons with AD [60], but cognitive impairment in persons with AD is found to correlate with reductions in D1 and D2 receptor binding and reduced dopamine availability in the amygdala and hippocampus [61]. Animal models of AD have been used to examine the association between dopamine release and cognitive function. In a study by Guzman-Ramos and colleagues [62], transgenic AD mice were found to perform more poorly than control mice on a learning and memory paradigm; this deficit was associated with lower levels of dopamine in the insular cortex. Following administration of a dopamine re-uptake inhibitor, increasing the extracellular concentration of dopamine, transgenic mice displayed enhanced performance on a test of long-term memory relative to transgenic mice receiving a saline solution [62]. Thus, enhancing dopaminergic function may reverse AD-related cognitive impairments.

Music has been shown to access and activate brain systems associated with reward and emotion [36, 63]. Imaging studies have shown enhanced activation of the hypothalamus, the NAc and the VTA in response to music listening [31]. Further, emotional responses to pleasant and unpleasant music have been shown to correlate with activation of paralimbic and cortical brain regions [36]. Research shows that activation in the NAc of the mesolimbic pathway following music listening significantly predicts the amount of money listeners are willing to pay to acquire additional music (i.e., music reward value) [64]. Further, the activation of other brain regions such as the VMPFC, amygdala, and auditory cortices predict music reward value only when functional connectivity with the NAc increased, suggesting that music can activate dopaminergic pathways, leading to enhancement of incentive salience [64].

Given that music can alter activity in brain pathways and structures that are associated with dopaminergic release, it may be postulated that music can be used to stimulate and strengthen dopaminergic pathways and interconnected brain structures that are commonly compromised in persons with AD. Enhancing motivation and reward circuits through music may therefore increase the incentive for learning new information, as shown in the study by Simmons-Stern and colleagues [4].

Dopaminergic projections from the hypothalamus to the pituitary gland are important for neuroendocrine activation and autonomic arousal. In a study by Sutoo and Akiyama [65], it was found that relaxing classical music reduced blood pressure in hypertensive rats and increased dopamine levels, suggesting that exposure to music may regulate autonomic functioning in the brain through enhancement of dopaminergic transmission. Consequently, it may be postulated that music listening increases dopaminergic function, which enhances emotional processing through autonomic activation while attaching a cognitive aspect of reward to the experience.

Music and physiological arousal

Music has the power to elicit intense emotional feelings and responses, which typically give rise to physiological changes through activation of the autonomic nervous system. High-arousal music (faster tempo, major mode, louder) can activate sympathetic activity of the autonomic nervous system, evidenced by increased skin conductance, respiration, heart rate, blood pressure, and vigilance [66, 67]. In contrast, relaxing music (slower tempo, low pitch, and is typically classical) can activate parasympathetic activity of the autonomic nervous system, resulting in attenuation of skin conductance, heart rate, blood pressure, and respiration [68]. Music then may regulate autonomic function, which in turn may be able to regulate attentional processes when encoding new information. Naturally, the level of arousal produced by music and the subsequent effects on attention are dependent on the basal physiological state of the individual.

Research shows that persons with AD report enhanced level of agitation [69], suggesting enhanced physiological arousal. In a randomized controlled trial, Ledger and Baker [69] randomized patients with AD to either a music therapy group or a no-music control group for a one-year period. The authors found that patients in the music group displayed reductions in agitation levels compared to patients in the non-music control. Similar benefits have been reported in patients with moderate-severe AD, such that music is found to significantly reduce subjective reports of anxiety and decrease incidence of agitated behavior following music therapy [43, 70]. Given that enhanced agitation and anxiety may impair attentional processes [71], it may be postulated that reducing anxiety and agitation may enhance attention at encoding, thus improving memory performance.

Some studies support the notion that arousal induced by music listening can improve cognitive function [72], and that arousal levels can modulate memory through attention processes [73]. In testing the Mozart Effect, which postulates a direct beneficial effect of music on cognitive function, Thompson, Schellenberg, and Husain [72] reported that performance on a spatial task improved following exposure to up-tempo happy music (Mozart sonata), compared with slow, sad sounding music (Albinoni’s Adagio) or silence. However, after controlling for level of arousal and mood, no improvements were found for Mozart’s sonata, thus suggesting that the effect of music on cognitive processing may be mediated through arousal.

Since persons with AD typically demonstrate lower performance on selective and divided attention tasks relative to their healthy counterparts, which further associate with declines in episodic memory performance [74], it may be postulated that modulating arousal levels may facilitate learning of new information.

Music and the default mode network

Although the above discussion focuses on potential mechanisms underlying the benefits of music at the neurotransmitter and physiological level, it is also worth considering mechanisms at the level of large-scale brain networks. The default mode network (DMN) is a system of interconnected brain regions that are active during resting state when individuals are awake and alert, but not actively engaged in a directed attentional task [75]. Brain structures thought to be part of this network include: The precuneus, the VMPFC and dorsolateral PFC, the posterior cingulate cortex (PCC) and areas of the parietal cortex and MTL. While the DMN is not completely understood, research suggests that it may be involved in self-referential processes such as introspection and autobiographical memory retrieval [76]. Controlling for variables such as age, whole brain volume, and clinical diagnosis, integrity of the DMN is found to correlate with measures of global cognitive function [77]. Patients with lesions in brain regions of the DMN such as the medial PFC, PCC, and MTL display impairment in autobiographical memory [78], which, as discussed above, is a common cognitive impairment noted in persons with AD.

There is extensive support in the literature for disrupted functional connectivity of the DMN in patients with AD [79, 80]. There is evidence of atrophy in MTL structures, PFC, PCC, and precuneus regions of the DMN in AD patients, which makes the network more vulnerable to network integration dysfunction [81]. Research examining the neuropsychiatric correlates of DMN activity in persons with AD suggests that increased connectivity in the anterior cingulate cortex and insula is associated with hyperactivity syndrome, including symptom presentation of agitation, irritability, and disinhibition [82].

Recent research demonstrates activation of the DMN when listening to music during moments of high activity where many instruments are simultaneously playing [83]. In a study that measured alpha electroencephalography rhythms as a proxy for DMN activity in a group of healthy younger adults, it was found that listening to music was associated with increased alpha rhythms, suggesting increased activation of the DMN [84]. This study also used fMRI and independent components analysis to look at connectivity between regions within and outside of the DMN during music listening. The authors noted increased connectivity and activation in frontal areas within the DMN during music listening, which may suggest enhanced introspective awareness when listening to music [84]. Further, the hippocampus was more active when participants were listening to music, which may suggest enhanced memory processing during music listening.

It has been suggested that the DMN is heavily involved in memory processes [79] and reduction in functional connectivity could be due to atrophy at the synaptic level as a consequence of AD, which in turn could influence how memory functions in AD. Further, recent evidence suggests that structures in the proposed DMN are important for autobiographical memory recall, which can be impaired in AD. Passively listening to music relevant to the self may potentially activate regions within this network, potentially increasing the functional connectivity to a more optimal level, and in turn, enhancing autobiographical memory recall. Preliminary evidence exists in relation to a link between listening to preferred music and activation of DMN regions. For instance, a recent fMRI study by Wilkins and colleagues [85] showed that when participants listen to their favorite music relative to songs that are not favorable, the hippocampus and auditory cortex are independently activated. Conversely, when participants listen to music they dislike, the hippocampus and auditory cortex are functionally connected. It may be postulated that the favorite music has existing emotional memories associated with it in relation to the self and does not necessarily need input from other DMN areas in order to process it. The auditory cortex could be involved initially, but listening to such familiar music would likely evoke memories, incorporating hippocampal activation. Altogether, the aforementioned research suggests that the DMN is an important brain network to target for music interventions; notably, it is suggested that music may engage and stimulate network connectivity, which may in turn enhance memory function in persons with AD.

CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE RESEARCH

AD is a debilitating disease accompanied by progressive deterioration of synaptic, structural, and neurochemical functioning which ultimately affects communication at the neural as well as systems level. Music listening can provide insight into disrupted connectivity in AD patients due to its activation of, and interactions between, different brain systems, which mediates affective and cognitive processes [35].

This paper outlines three potential mechanisms underlying the effect of music on memory in persons with AD. These mechanisms are not independent, but allow for the examination of music interventions at different levels of analysis, including the neurotransmitter level, autonomic nervous system level, and the more comprehensive and broad level of neuronal connectivity. In order to truly understand how music enhances memory in persons with neurodegenerative disease with the intention of creating clinical interventions, it is imperative to understand how music affects these underlying systems and networks.

Future research should consider possible methodological limitations of previous work, including type of music. Many of the studies presented used experimenter-selected music, and only very few studies to date have directly compared the use of self-selected familiar music to experimenter selected music in relation to autobiographical memory recall in AD. If patients with AD were permitted to choose their own music, or have a close family member select it based on their preference, the music may be more salient and thus the intervention potentially more effective. Some studies do use participant-selected music, but details of the music parameters are not disclosed, making the study design difficult to replicate. Additional research is imperative to determine why familiar, or self-selected music appears to be superior in order to create the most effective interventions. Similarly, future research could compare the effectiveness of actively singing or playing musical instruments relative to passive listening and any resulting effects on cognition and mood. A recent qualitative study by Osman and colleagues [86] provides preliminary evidence that participating in a singing group has a positive effect on mood and well-being in patients with dementia and their caregivers, as well as helping the patient become more accepting of their diagnosis. This study is an important starting point, but more empirical research with larger samples of patients is necessary to further investigate the benefit of such programs in the AD population.

The majority of studies to date have focused on patients with mild forms of AD and thus it cannot be assumed that the beneficial effects of music will extend to patients at a more severe disease stage. Progressive atrophy of neuronal regions, such as the amygdala, which is particularly important for processing and understanding of emotions through communication with other brain regions [15], may render music ineffective [87]. Additional research is needed to determine the efficacy of music as a memory enhancer across disease state.

Future research is also needed to determine whether music serves to strengthen connectivity and neuronal activation of affected brain areas, or whether music targets preserved brain processes that may be spared in AD [8 , 88]. Supporting the latter, a recent neuroimaging study by Jacobsen and colleagues [89] investigated the neural substrates involved in encoding music in healthy adults and showed that listening to well-known musical excerpts activated the caudal anterior cingulate and the pre-supplementary motor area; these brain regions were not activated when participants listened to unknown or recently encoded music excerpts [89]. Investigating these brain regions in patients with AD, Jacobson and colleagues [89] found that these aforementioned neural regions displayed the lowest gray matter atrophy and hypometabolism within the entire brain, suggesting that the functional capacity of these areas is relatively preserved in AD. Thus, as AD progresses and neuronal atrophy and disconnectivity of the DMN continue to ensue, individuals may rely on different memory processes or show improvement only in certain memory domains.

Future research is needed to examine whether music may be used to rehabilitate different aspects of cognitive function depending on disease severity. For instance, music interventions that target recollection rather than recognition memory might only be effective in persons with Mild Cognitive Impairment (MCI) or early stage AD [4]; whereas music listening in later stages of the disease may be directed toward music improving memory through familiarity with the goal of helping the patient regain a sense of identity and potentially improving quality of life.

Much of the available empirical research is based on assessment in acute time periods. While some studies have assessed the effectiveness of music across varying periods of time from two months to two years, these studies have focused on the beneficial effects of music on cardiovascular health [90], agitation [91], and psychopathology in AD [92 –94]. While one study by Suzuki and colleagues [95] evaluated the effect of an 8-week music intervention in 10 patients with dementia (8 AD, 2 vascular dementia), the assessment of cognitive function was limited, having only administered the Mini-Mental State Exam. Further, there was no follow-up post intervention. A main objective and focus of future research should be to look beyond the potential acute behavioral effects of music and to investigate longitudinal effects of music on maintenance of cognitive function and brain plasticity in AD. Future research should examine the neural mechanisms underlying the beneficial cognitive effects of music and outline long-term neuronal changes stemming from music exposure. Such research is needed to provide insight into the development and application of effective non-pharmacological treatments for individuals with AD. Given the increasing aging population coupled with an increasing incidence of AD, further research aimed at the identification of music’s mechanisms of action in relation to memory enhancement is imperative. With the addition of more empirical research, the future of music as a way to enhance aspects of memory and quality of life from a non-pharmaceutical approach holds much promise for development of interventions focused on the maintenance of cognitive and psychological well-being in persons with AD.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/15-0998r1).

References

World Health Organization and Alzheimer’s Disease International (2012) Dementia: A public health priority. http://www.who.int/mental_health/publications/dementia_report_2012/en/.

Koelsch

, Fritz

, DY

, Muller

, Friederici

(2006) Investigating emotion with music: An fMRI study. Hum Brain Mapp 27, 239–250.

Ferreri

, Aucouturier

, Muthalib

, Bigand

, Bugaiska

(2013) Music improves verbal memory encoding while decreasing prefrontal cortex activity: An fNIRS study. Front Hum Neurosci 7, 779.

Simmons-Stern

, Budson

, Ally

(2010) Music as a memory enhancer in patients with Alzheimer’s disease. Neuropsychologia 48, 3164–3167.

Petrovsky

, Cacchione

, George

(2015) Review of the effect of music interventions on symptoms of anxiety and depression in older adults with mild dementia. Int Psychogeriatr 27, 1661–1670.

Blackburn

, Bradshaw

(2014) Music therapy for service users with dementia: A critical review of the literature. J Psychiatr Ment Health Nurs 21, 879–888.

Baird

, Samson

(2015) Music and dementia. Prog Brain Res 217, 207–235.

Baird

, Samson

(2009) Memory for music in Alzheimer’s disease: Unforgettable? Neuropsychol Rev 19, 85–101.

Samson

, Clement

, Narme

, Schiaratura

, Ehrle

(2015) Efficacy of musical interventions in dementia: Methodological requirements of nonpharmacological trials. Ann N Y Acad Sci 1337, 249–255.

10.

McDermott

, Crellin

, Ridder

, Orrell

(2013) Music therapy in dementia: A narrative synthesis systematic review. Int J Geriatr Psychiatry 8, 781–794.

11.

Geula

, Mesulam

, Saroff

, Wu

(1998) Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease. J Neuropath Exp Neur 57, 63–75.

12.

Perry

, Tomlinson

, Blessed

, Bergmann

, Gibson

, Perry

(1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2, 1457–1459.

13.

de Toledo-Morrell

, Goncharova

, Dickerson

, Wilson

, Bennett

(2000) From healthy aging to early Alzheimer’s disease: In vivo detection of entorhinal cortex atrophy. Ann N Y Acad Sci 911, 240–253.

14.

Killiany

, Hyman

, Gomez-Isla

, Moss

, Kikinis

, Jolesz

, Tanzi

, Jones

, Albert

(2002) MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 58, 1188–1196.

15.

Poulin

, Dautoff

, Morris

, Barrett

, Dickerson

, Alzheimer’s Disease Neuroimaging Initiative (2011) Amygdala atrophy is prominent in early Alzheimer’s disease and relates to symptom severity. Psychiatry Res 194, 7–13.

16.

LaBar

, Cabeza

(2006) Cognitive neuroscience of emotional memory. Nat Rev Neurosci 7, 54–64.

17.

Klein-Koerkamp

, Heckemann

, Ramdeen

, Moreaud

, Keignart

, Krainik

, Hammers

, Baciu

, Hot

, Alzheimer’s disease Neuroimaging Initiative (2014) Amygdalar atrophy in early Alzheimer’s disease. Curr Alzheimer Res 11, 239–252.

18.

Pagnoni

, Zink

, Montague

, Berns

(2002) Activity in human ventral striatum locked to errors of reward prediction. Nat Neurosci 5, 97–98.

19.

Everitt

, Parkinson

, Olmstead

, Arroyo

, Robledo

, Robbins

(1999) Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems. Ann N Y Acad Sci 877, 412–438.

20.

Lehericy

, Hirsch

, Cervera

, Hersh

, Hauw

, Ruberg

, Agid

(1989) Selective loss of cholinergic neurons in the ventral striatum of patients with Alzheimer disease. Proc Natl Acad Sci U S A 86, 8580–8584.

21.

Foundas

, Leonard

, Mahoney

, Agee

, Heilman

(1997) Atrophy of the hippocampus, parietal cortex, and insula in Alzheimer’s disease: A volumetric magnetic resonance imaging study. Neuropsychiatry Neuropsychol Behav Neurol 10, 81–89.

22.

Craig

(2009) How do you feel–now? The anterior insula and human awareness. Nat Rev Neurosci 10, 59–70.

23.

Gregory

, Hodges

(1996) Clinical features of frontal lobe dementia in comparison to Alzheimer’s disease. J Neural Transm 47(Suppl), 03–123.

24.

Greene

, Hodges

, Baddeley

(1995) Autobiographical memory and executive function in early dementia of Alzheimer type. Neuropsychologia 3, 1647–1670.

25.

Seidl

, Lueken

, Thomann

, Geider

, Schroder

(2011) Autobiographical memory deficits in Alzheimer’s disease. J Alzheimers Dis 27, 567–574.

26.

Fargeau

, Jaafari

, Ragot

, Houeto

, Pluchon

, Gil

(2010) Alzheimer’s disease and impairment of the Self. Conscious Cog 19, 969–976.

27.

Lyketsos

, Lopez

, Jones

, Fitzpatrick

, Breitner

, DeKosky

(2002) Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: Results from the cardiovascular health study. JAMA 288, 1475–1483.

28.

Krumhansl

(1997) An exploratory study of musical emotions and psychophysiology. Can J Exp Psychol 51, 336–353.

29.

Krout

(2007) Music listening to facilitate relaxation and promote wellness: Integrated aspcets of our neurophysiological responses to music. Arts Psychother 34, 134–141.

30.

Limb

(2006) Structural and functional neural correlates of music perception. Anat Rec A Discov Mol Cell Evol Biol 288, 435–446.

31.

Menon

, Levitin

(2005) The rewards of music listening: Response and physiological connectivity of the mesolimbic system. Neuroimage 28, 175–184.

32.

Risacher

, Saykin

(2013) Neuroimaging biomarkers of neurodegenerative diseases and dementia. Semin Neurol 33, 386–416.

33.

Wallis

(2007) Orbitofrontal cortex and its contribution to decision-making. Annu Rev Neurosci 30, 31–56.

34.

Delgado

, Nearing

, Ledoux

, Phelps

(2008) Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Neuron 59, 829–838.

35.

Peretz

(2010), Towards a Neurobiology of Musical Emotions Oxford University Press Oxford, UK.

36.

Blood

, Zatorre

(2001) Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proc Natl Acad Sci U S A 98, 11818–11823.

37.

Watanabe

, Yagishita

, Kikyo

(2008) Memory of music: Roles of right hippocampus and left inferior frontal gyrus. Neuroimage 39, 483–491.

38.

Beatty

(1999) Preserved cognitive skills in dementia: Implications for geriatric medicine. J Okla State Med Assoc 92, 10–12.

39.

Price

, Ko

, Wade

, Tsou

, McKeel

, Morris

(2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58, 1395–1402.

40.

Cowles

, Beatty

, Nixon

, Lutz

, Paulk

, Ross

(2003) Musical skill in dementia: A violinist presumed to have Alzheimer’s disease learns to play a new song. Neurocase 9, 493–503.

41.

Cuddy

, Duffin

(2005) Music, memory, and Alzheimer’s disease: Is music recognition spared in dementia, and how can it be assessed? Med Hypotheses 64, 229–235.

42.

Schulkind

, Hennis

, Rubin

(1999) Music, emotion, and autobiographical memory: They’re playing your song. Mem Cognit 27, 948–955.

43.

Irish

, Cunningham

, Walsh

, Coakley

, Lawlor

, Robertson

, Coen

(2006) Investigating the enhancing effect of music on autobiographical memory in mild Alzheimer’s disease. Dement Geriatr Cogn 22, 108–120.

44.

Meilan Garcia

, Iodice

, Carro

, Sanchez

, Palmero

, Mateos

(2012) Improvement of autobiographic memory recovery by means of sad music in Alzheimer’s disease type dementia. Aging-Clin Exp Res 24, 227–232.

45.

El Haj

, Fasotti

, Allain

(2012) The involuntary nature of music-evoked autobiographical memories in Alzheimer’s disease. Conscious Cogn 21, 238–246.

46.

El Haj

, Postal

, Allain

(2012) Music enhances autobiographical memory in mild Alzheimer’s disease. Educ Gerontol 38, 30–41.

47.

El Haj

, Clement

, Fasotti

, Alain

(2013) Effects of music on autobiographical verbal narration in Alzheimer’s disease. J Neurolinguist 26, 691–700.

48.

Baird

, Samson

(2014) Music evoked autobiographical memory after severe acquired brain injury: Preliminary findings from a case series. Neuropsychol Rehabil 24, 125–143.

49.

Cuddy

, Sikka

, Vanstone

(2015) Reservation of musical memory and engagement in healthy aging and Alzheimer’s disease. Ann N Y Acad Sci 1337, 223–231.

50.

Janata

, Tomic

, Rakowski

(2007) Characterization of music-evoked autobiographical memories. Memory 15, 845–860.

51.

Arroyo-Anllo

, Diaz

, Gil

(2013) Familiar music as an enhancer of self-consciousness in patients with Alzheimer’s disease. Biomed Res Int 752965.

52.

Simmons-Stern

, Deason

, Brandler

, Frustace

, O’Connor

, Ally

, Budson

(2012) Music-based memory enhancement in Alzheimer’s disease: Promise and limitations. Neuropsychologia 50, 3295–3303.

53.

Gagnon

, Peretz

, Fulop

(2009) Musical structural determinants of emotional judgments in dementia of the Alzheimer type. Neuropsychology 23, 90–97.

54.

Wise

(2004) Dopamine, learning and motivation. Nat Rev Neurosci 5, 483–494.

55.

Demarest

, Moore

(1979) Comparison of dopamine synthesis regulation in the terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons. J Neural Transm 46, 263–277.

56.

Berridge

, Robinson

(1998) What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience? Brain Res Rev 28, 309–369.

57.

Knutson

, Fong

, Adams

, Varner

, Hommer

(2001) Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport 12, 3683–3687.

58.

Posner

, Russell

, Peterson

(2005) The circumplex model of affect: An integrative approach to affective neuroscience, cognitive development, and psychopathology. Dev Psychopathol 17, 715–734.

59.

Gibb

, Mountjoy

, Mann

, Lees

(1989) The substantia nigra and ventral tegmental area in Alzheimer’s disease and Down’s syndrome. J Neurol Neurosurg Psychiatry 52, 193–200.

60.

Wolfe

, Katz

, Albert

, Almozlino

, Durso

, Smith

, Volicer

(1990) Neuropsychological profile linked to low dopamine: In Alzheimer’s disease, major depression, and Parkinson’s disease. J Neurol Neurosurg Psychiatry 53, 915–917.

61.

, Yan

, Zhou

, Li

, Gao

, Xia

, Wang

(2012) Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 97, 1–13.

62.

Guzman-Ramos

, Moreno-Castilla

, Castro-Cruz

, McGaugh

, Martinez-Coria

, LaFerla

, Bermudez-Rattoni

(2012) Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer’s disease. Learn Mem 19, 453–460.

63.

Salimpoor

, Benovoy

, Larcher

, Dagher

, Zatorre

(2011) Anatomically distinct dopamine release during anticipation and experience of peak emotion to music. Nat Neurosci 14, 257–262.

64.

Salimpoor

, van den Bosch

, Kovacevic

, McIntosh

, Dagher

, Zatorre

(2013) Interactions between the nucleus accumbens and auditory cortices predict music reward value. Science 340, 216–219.

65.

Sutoo

, Akiyama

(2004) Music improves dopaminergic neurotransmission: Demonstration based on the effect of music on blood pressure regulation. Brain Res 1016, 255–262.

66.

Nater

, Abbruzzese

, Krebs

, Ehlert

(2006) Sex differences in emotional and psychophysiological responses to musical stimuli. Int J Psychophysiol 62, 300–308.

67.

Khalfa

, Isabelle

, Jean-Pierre

, Manon

(2002) Event-related skin conductance responses to musical emotions in humans. Neurosci Lett 328, 145–149.

68.

Knight

, Rickard Ph

(2001) Relaxing music prevents stress-induced increases in subjective anxiety, systolic blood pressure, and heart rate in healthy males and females. J Music Ther 38, 254–272.

69.

Ledger

, Baker

(2007) An investigation of long-term effects of group music therapy on agitation levels of people with Alzheimer’s disease. Aging Ment Health 11, 330–338.

70.

Svansdottir

, Snaedal

(2006) Music therapy in moderate and severe dementia of Alzheimer’s type: A case-control study. Int Psychogeriatr 18, 613–621.

71.

Eysenck

, Derakshan

, Santos

, Calvo

(2007) Anxiety and cognitive performance: Attentional control theory. Emotion 7, 336–353.

72.

Thompson

, Schellenberg

, Husain

(2001) Arousal, mood, and the Mozart effect. Psychol Sci 12, 248–251.

73.

Sharot

, Phelps

(2004) How arousal modulates memory: Disentangling the effects of attention and retention. Cogn Affect Behav Neurosci 4, 294–306.

74.

Perry

, Watson

, Hodges

(2000) The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer’s disease: Relationship to episodic and semantic memory impairment. Neuropsychologia 38, 252–271.

75.

Raichle

, MacLeod

, Snyder

, Powers

, Gusnard

, Shulman

(2001) A default mode of brain function. Proc Natl Acad Sci U S A 98, 676–682.

76.

D’Argembeau

, Collette

, Van der Linden

, Laureys

, Del Fiore

, Degueldre

, Luxen

, Salmon

(2005) Self-referential reflective activity and its relationship with rest: A PET study. Neuroimage 25, 616–624.

77.

Spreng

, Sepulcre

, Turner

, Stevens

, Schacter

(2013) Intrinsic architecture underlying the relations among the default, dorsal attention, and frontoparietal control networks of the human brain. J Cogn Neurosci 25, 74–86.

78.

Philippi

, Tranel

, Duff

, Rudrauf

(2015) Damage to the default mode network disrupts autobiographical memory retrieval. Soc Cogn Affect Neur 10, 318–326.

79.

Buckner

, Snyder

, Shannon

, LaRossa

, Sachs

, Fotenos

, Sheline

, Klunk

, Mathis

, Morris

, Mintun

(2005) Molecular, structural, and functional characterization of Alzheimer’s disease: Evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25, 7709–7717.

80.

Sorg

, Riedl

, Muhlau

, Calhoun

, Eichele

, Laer

, Drzezga

, Forstl

, Kurz

, Zimmer

, Wohlschlager

(2007) Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 104, 18760–18765.

81.

Seeley

, Crawford

, Zhou

, Miller

, Greicius

(2009) Neurodegenerative diseases target large-scale human brain networks. Neuron 62, 42–52.

82.

Balthazar

, Pereira

, Lopes

, da Silva

, Coan

, Campos

, Duncan

, Stella

, Northoff

, Damasceno

, Cendes

(2014) Neuropsychiatric symptoms in Alzheimer’s disease are related to functional connectivity alterations in the salience network. Hum Brain Mapp 35, 1237–1246.

83.

Alluri

, Toiviainen

, Jaaskelainen

, Glerean

, Sams

, Brattico

(2012) Large-scale brain networks emerge from dynamic processing of musical timbre, key and rhythm. Neuroimage 59, 3677–3689.

84.

Kay

, Meng

, Difrancesco

, Holland

, Szaflarski

(2012) Moderating effects of music on resting state networks. Brain Res 1447, 53–64.

85.

Wilkins

, Hodges

, Laurienti

, Steen

, Burdette

(2014) Network science and the effects of music preference on functional brain connectivity: From Beethoven to Eminem. Sci Rep 4, 6130.

86.

Osman

, Tischler

, Schneider

(2014) ‘Singing for the Brain’: A qualitative study exploring the health and well-being benefits of singing for people with dementia and their carers. Dementia London, doi: 10.1177/1471301214556291

87.

Hamann

, Monarch

, Goldstein

(2000) Memory enhancement for emotional stimuli is impaired in early Alzheimer’s disease. Neuropsychology 14, 82–92.

88.

Drapeau

, Gosselin

, Gagnon

, Peretz

, Lorrain

(2009) Emotional recognition from face, voice, and music in dementia of the Alzheimer type. Ann N Y Acad Sci 1169, 342–345.

89.

Jacobsen

, Stelzer

, Fritz

, Chetelat

, La Joie

, Turner

(2015) Why musical memory can be preserved in advanced Alzheimer’s disease. Brain 138, 2438–2450.

90.

Takahashi

, Matsushita

(2006) Long-term effects of music therapy on elderly with moderate/severe dementia. J Music Ther 43, 317–333.

91.

Gerdner

(2000) Effects of individualized versus classical “relaxation” music on the frequency of agitation in elderly persons with Alzheimer’s disease and related disorders. Int Psychogeriatr 12, 49–65.

92.

Raglio

, Bellelli

, Traficante

, Gianotti

, Ubezio

, Villani

, Trabucchi

(2008) Efficacy of music therapy in the treatment of behavioral and psychiatric symptoms of dementia. Alzheimer Dis Assoc Disord 22, 158–162.

93.

Raglio

, Bellelli

, Traficante

, Gianotti

, Ubezio

, Gentile

, Villani

, Trabucchi

(2010) Efficacy of music therapy treatment based on cycles of sessions: A randomised controlled trial. Aging Ment Health 14, 900–904.

94.

Narme

, Clement

, Ehrle

, Schiaratura

, Vachez

, Courtaigne

, Munsch

, Samson

(2014) Efficacy of musical interventions in dementia: Evidence from a randomized controlled trial. J Alzheimers Dis 38, 359–369.

95.

Suzuki

, Kanamori

, Watanabe

, Nagasawa

, Kojima

, Ooshiro

, Nakahara

(2004) Behavioral and endocrinological evaluation of music therapy for elderly patients with dementia. Nurs Health Sci 6, 11–18.