Effect of Music on Attention and Prospective Memory in Hepatic Encephalopathy
Effect of Music on Attention and Prospective Memory in Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a potentially reversible, metabolically caused complication of
 acute or chronic liver diseases such as cirrhosis. Due to the diseased liver's inability to
 remove toxins such as ammonia, which is produced in the gastrointestinal tract, the ammonia
 accumulates in the brain and causes forgetfulness, confusion, disorientation, concentration
 and memory problems, changes in mood, decreased alertness and responsiveness, changes in
 sleep habits, muscle tremors and stiffness, speech impairments, uncontrollable movements,
 agitation.

 This study will examine music as a possible external factor that could contribute to
 impairment in attention and progressive memory in cirrhotic patients while driving.
 Sustaining attention is important for learning and remembering new information, for e.g.
 keeping the car within lane and paying attention to cyclists and pedestrians. Prospective
 memory is the ability to remember to perform previously intended tasks at the appropriate
 time or occasion, for instance remembering the correct exit while driving on the highway.
 Impairment in any of these areas may result in serious consequences for patient with
 cirrhosis. There is evidence that some subsets of cirrhotic patients have a diminished
 ability to drive and significantly more motor vehicle crashes and traffic violations. In
 these patients, listening to music while driving may further jeopardize their driving
 ability, which in turn may lead to reduced quality of life and increased medical costs (from
 motor vehicle accidents).

 This is a cross-sectional study designed to determine if there is any effect of listening to
 music on attention and prospective memory in patients with cirrhosis. For these purposes,
 subjects will be asked to come for one study visit, which will last approximately 2 hours.
 During this visit, subjects will undergo a series of screening procedures (consent,
 assignment of subject identification number, demographics, medical history, physical
 examination, vitals, height, weight, and eligibility assessment). If they are found eligible,
 subjects will undergo several neuropsychological assessments to measure any effect of music
 on attention and prospective memory. These assessments include including Number Connection
 Test (NCT), Digit Symbol Test (DST), Cambridge Prospective Memory Test (CAMPROMPT) and
 Inhibitory Control Test (ICT).
Cirrhosis occurs when scar tissue replaces healthy liver tissue, partially blocking blood
 flow and preventing the liver's ability to control infections, removes bacteria and toxins
 from the blood, and to produce proteins to regulate blood clotting and bile to absorb fats
 and fat-soluble vitamins. With an estimated prevalence between five and ten percent,
 cirrhosis is the twelfth leading cause of death by disease, leading to 27,000 deaths per
 year. Heavy alcohol consumption and hepatotropic viruses (hepatitis B and C) are the major
 contributors to this disease's prevalence (NDDIC, 2003).

 Hepatic encephalopathy (HE) is a potentially reversible, metabolically caused complication of
 acute or chronic liver diseases such as cirrhosis, which is characterized by neuropsychiatric
 abnormalities. Nearly 70% of cirrhotic patients experience mild levels of HE and
 approximately 30% of end-stage patients experience significant HE symptoms, many approaching
 coma (Mullen et al., 1999). Although the pathophysiology of HE is not yet clearly understood,
 the accumulation of ammonia in the brain due to the liver's inability to remove toxins
 (including ammonia) is thought to play a key role in the pathogenesis of HE. Other factors,
 which are not mutually exclusive, include increased GABA-ergic tone, selective alterations of
 the blood-brain barrier permeability and changes in neurotransmitter systems. The broad
 spectrum of symptoms in HE include forgetfulness, confusion, disorientation, concentration
 and memory problems, changes in mood, decreased alertness and responsiveness, changes in
 sleep habits, muscle tremors and stiffness, speech impairments, uncontrollable movements,
 agitation (Ferenci et al., 2002).

 The diagnosis of HE is essentially based on clinical history and laboratory findings such as
 elevated ammonia levels. Additionally, specialized psychometric tests such as the number
 connection test (NCT), Digit Symbol Test (DST) and Psychometric Hepatic Encephalopathy Score
 (PHES) have been used in quantifying the minor deficits that may be present in patients with
 early HE.

 Minimal hepatic encephalopathy (MHE) is a category of early HE without any overt
 neuropsychiatric symptoms but with subtle cognitive deficits (Ferenci et al., 1998). It is a
 common complication of cirrhosis and has been reported in 20% to 74% of patients (Dhiman et
 al., 2010), depending on the test used for diagnosis. It results in deficits in specific
 cognitive domains such as attention, vigilance, response inhibition, executive function and
 prospective memory. These deficits are often not apparent from a routine neurological exam or
 MMSE but can be detected on psychometric testing. The prompt identification and treatment of
 MHE are essential because MHE predicts progression to overt HE and impairs the capacity to
 drive which can have a significant impact on patients' quality of life (Romero-Gomez et al.,
 2001; Wein et al, 2004) .

 Treatment of HE with or without liver transplantation has been shown to reverse the cognitive
 deficits and improve quality of life (Prasad et al., 2007; Sidhu et al., 2011). Although the
 PHES and NCT are the gold standard for diagnosing MHE, their utility is limited due to
 expensive copyright, a need for trained psychologists and the lack of reimbursements from
 insurance companies. A simpler test would therefore be beneficial to internists who could
 easily implement it in the clinic setting.

 The inhibitory control task (ICT) is a computerized psychometric test that has been
 introduced recently as a diagnostic tool for MHE. It measures the ability to sustain
 attention and to inhibit responses to relevant stimuli, 2 basic cognitive domains that are
 impaired in MHE. During the ICT, the patient is presented with a continuous stream of letters
 at 500-ms intervals and interspersed within these letters are the letters X and Y. Subjects
 are instructed to only respond when the letters "X" and "Y" are alternated (called targets),
 independent of the letters between them. In contrast, patients are instructed to refrain from
 responding, i.e. inhibit their response, when "X" and "Y" are not alternating (called lures).
 Higher rates of target response, lower rates of lure response and shorter reaction times
 indicate better attention and response inhibition. One study by Bajaj et al. (2008) showed
 the ICT to be a reliable test with 87% sensitivity for the diagnosis of MHE, with MHE
 patients having higher ICT lures and lower targets compared to patients without MHE.

 Patients with MHE have deficits in attention and prospective memory which are cognitive
 domains that are important to activities such as driving. Sustaining attention is important
 for learning and remembering new information, for e.g. keeping the car within the lane while
 driving and paying attention to pedestrians and cyclists. Prospective memory involves both
 working memory (to formulate, initiate, and modify plans of action) and retrospective memory
 (to recall what needs to be done at a particular time or in response to an external cue), for
 instance, remembering the correct exit while driving on the highway. The act of driving
 requires the ability to sustain attention and utilize prospective memory under stressful
 conditions. Impairment in any of these areas may result in serious consequences for patient
 with chronic liver disease, such as cirrhosis. Indeed, some studies of cirrhotic patients
 have shown that those with MHE have a diminished ability to drive and significantly more
 motor vehicle crashes and traffic violations than those without MHE (Bajaj et al., 2007,
 2009). The reasons behind this are thought to be not only the obvious cognitive deficits, but
 also a greater tendency to fatigue at the wheel and poor insight into the cognitive
 deficiencies (Kircheis et al., 2009). In fact, driving simulator tests and questionnaire
 surveys have shown that patients with MHE who have been diagnosed using the ICT have impaired
 navigational skills and significantly higher crash rates (Bajaj et al., 2008, 2009).

 In addition to the potential value of the ICT in detecting MHE, the test may be useful in
 uncovering temporary insults to attention and working memory that may arise in the presence
 of external stimuli such as music. Listening to music while driving is a pervasive practice
 and the relationship between background music and driving performance has been studied in the
 past (Unal et al., 2012; van der Zwaag et al., 2012). However these studies did not
 specifically address patients with cirrhosis, who are a population at higher risk of traffic
 accidents. The hypothesis of our study are (1) cirrhotic patients with MHE are expected to
 have lower ICT scores than patients without MHE and (2) these deficits are expected to worsen
 in the presence of music, suggesting music as a possible factor that could contribute to
 impaired attention and working memory, and hence impaired driving ability in cirrhotic
 patients. To this end, various types of music, including classical and heavy metal, will be
 used as a means of distracting cirrhotic patients while they are administered the ICT, to
 determine if there is any effect of listening to music on ICT scores. In addition to the ICT,
 the Digit Symbol Test, Number Connection Test, Cambridge Prospective Memory Test (CAMPROMPT),
 Stroop test, Fisk Fatigue Impact Scale and Epworth Sleepiness Scale will also be administered
 to quantify the degree of HE. While the use of ICT may not be appropriate for definitively
 predicting driving fitness, it may be valuable in uncovering deficits in attention and memory
 that arise while listening to music, which may ultimately aid in the counseling and education
 of patients regarding safe driving practices.
Inclusion Criteria:

 -  Ambulatory patient with cirrhosis

 -  Able to provide informed consent

 Exclusion Criteria:

 -  History of alcohol abuse within six months

 -  Active gastrointestinal bleeding

 -  Unable to provide informed consent