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Several years ago, neurologist Masud Husain of the University of Oxford received an unusual referral letter from a general practitioner, describing a 41-year-old man who had, according to his friends, become extremely boring after suffering a stroke. Once outgoing and exuberant, he suddenly seemed to lack the impetus to do anything—he got fired from his job, lost interest in socializing with others, and spent most days sitting around at home, but “couldn’t be bothered” to cook for himself, or even listen to music, despite previously being very enthusiastic about it.
Brain scans revealed damage to the basal ganglia, a set of deep brain structures that use the neurotransmitter dopamine to signal reward and motivation in regions that connect with the prefrontal cortex. This caused the patient to become insensitive to reward, leading to pathological apathy. Drugs that increased dopamine levels partially restored this, however, increasing the patient’s motivation and his social interactions.
This was an extremely rare case, but it is now becoming increasingly clear that disorders of motivation such as pathological apathy and impulsive decision-making are common in a variety of brain disorders, affecting a significant minority of people who have neurodegenerative diseases such as Alzheimer’s and Parkinson’s, as well as those who have had a stroke or traumatic injury and those suffering from neuropsychiatric conditions such as depression and schizophrenia. Husain and other leading researchers in the field discussed the latest developments in a symposium at the biennial meeting of the British Neuroscience Association in Birmingham, UK earlier this month.
Cognitive neuroscientist and Dana Alliance for Brain Initiatives member Trevor Robbins of the University of Cambridge, who co-chaired the symposium with Husain, described what is currently known about the neural and psychological mechanisms underlying impulsivity, defined as the tendency to act prematurely and without foresight because of an inability to inhibit certain responses or a lack of self-control.
“Impulsivity is the bedrock of several neuropsychiatric disorders,” said Robbins. “For example, attention-deficit hyperactivity disorder [ADHD] numbers impulsivity among its symptoms.” It is also seen in patients with mania and personality disorders, and can occur in people who have Parkinson’s disease, as a side effect of their medication.
In 2003, Robbins and his colleagues reported that the ability to inhibit inappropriate responses is disrupted by damage to part of the prefrontal cortex called the inferior frontal gyrus. Based on these findings, Robbins argues that impulsivity occurs as a result of dysfunction in circuitry connecting the brain’s reward pathway to the prefrontal cortex, which is involved in so-called executive functions such as planning and decision-making, affecting the anticipation of reward and behaviors linked to it.
Substance abusers also have an impulsive tendency. Robbins and his colleagues have recently found that drug addiction is linked to abnormalities in circuits linking the brain’s reward pathway to the prefrontal cortex, which are also seen in addicts’ biological siblings who have no history of drug abuse. “The question is: Is the tendency for impulsivity a consequence of drug use, or a predisposing factor? These findings suggest that it is present in the family even before any drug-taking begins,” said Robbins. [See: How Should Society Treat Addiction?]
Psychologist Ratko Radakovic of the University of Edinburgh noted the high prevalence of apathy in patients with neurodegenerative disease. It occurs in up to 40 percent of those diagnosed with amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, and 60–90 percent of patients with Alzheimer’s and frontotemporal dementia (FTD). It affects the quality of life of both patients and their caregivers, and increases the caregivers’ burden. In all of these conditions, apathy is associated with faster disease progression. It is under-recognized by clinicians, however, and can be difficult to measure in ALS and other conditions that cause physical disability.
Apathy had been considered as a single symptom, but now can be classified into different subtypes. Radakovic and his colleagues subdivide it into three categories: emotional apathy, or an indifference to other people and events; executive apathy, a lack of motivation to plan and organize; and initiation apathy, a lack of motivation to self-generate thoughts and behavior.
They have also developed the dimensional apathy scale, a 24-item questionnaire designed to measure the three apathy subtypes in patients with motor dysfunction. Using this scale, they have found that ALS is characterised by increased initiation apathy and, somewhat surprisingly, reduced emotional apathy, compared with people without ALS.
“We found that Parkinson’s disease patients have more initiation and executive apathy, and this significantly impairs their daily life,” said Radakovic. Alzheimer’s patients, by contrast, score highly on all three dimensions, but a comparison of the patients’ responses with those of their caregivers showed that they seem to lack awareness of their executive and initiation apathy.
The researchers have also administered the dimensional apathy scale to a smaller number of FTD patients, and found that they, too, exhibit global apathy, but score even more highly on emotional apathy than Alzheimer’s patients. “This needs to be explored further as they could be used to design coping strategies and interventions that help people to motivate themselves through this complicated symptom,” said Radakovich.
Ciara McCabe of Reading University then described her work using functional neuroimaging to investigate reward processing in the brains of people with depression.
“Depression is maintained by a negative bias, or an over-processing of negative information about the self or environment,” McCabe said. “The psychological and drug treatments we have only work in about 30-50 percent of people, and one of the reasons for that could be that there are other symptoms that aren’t being targeted.” [See: The Link Between Depression, Sleep, and Stress and Does Depression Change the Way People Perceive the World?]
One of these is anhedonia, or an inability to experience pleasure and rewards, one of the two main criteria for a diagnosis of depression. A better understanding of reward processing in depression could therefore lead to novel therapies and treatments.
Earlier this year, McCabe and her colleagues published preliminary evidence that differences in reward processing could identify adolescents at risk of developing full-blown depression. They recruited 33 adolescents with depressive symptoms, 16 deemed to be at high risk, as determined by a mood questionnaire, and 17 at low risk, and scanned their brains while they first viewed images of, and then ate, pleasant and unpleasant foods.
They found that those at high risk of developing depression had blunted brain responses when viewing and eating both types of food, suggesting that they both underestimate the value of anticipated rewards and are less sensitive to rewards they receive.
“Anticipation of reward seems to be a marker for depression,” said McCabe. “If we can decipher how the different types of reward processing are altered, maybe interventions could target them.”
Recent research from Husain’s lab is revealing more about the neural computations underlying decision-making, and how it might be altered in neurological disease. Husain and his colleagues recently reported that the amount of effort needed to obtain a reward plays a big role in the choices we make, and they have also found that apathy in patients with Parkinson’s disease is associated with an insensitivity to reward, too.
In most people, reward anticipation causes pupil dilatation, with the size of the reward being directly related to the size of the response. Apathetic Parkinson’s patients show a reduced pupillary response to rewards, however, and the size of the reduction predicts the severity of apathy symptoms. These pupillary responses could therefore provide an objective way of monitoring apathy in patients.
“Apathetic individuals [with Parkinson’s disease] have a blunted response to reward, but those who are non-apathetic actually show a hypersensitivity to reward when they’re on [their medication],” said Husain. “That might be related to why some individuals are more likely to show impulsive behaviors.”