Robert Adam

Dopamine reverses reward insensitivity in apathy following globus pallidus lesions

Apathy is a complex, behavioural disorder associated with reduced spontaneous initiation of actions. Although present in mild forms in some healthy people, it is a pathological state in conditions such as Alzheimers and Parkinsons disease where it can have profoundly devastating effects. Understanding the mechanisms underlying apathy is therefore of urgent concern but this has proven difficult because widespread brain changes in neurodegenerative diseases make interpretation difficult and there is no good animal model. Here we present a very rare case with profound apathy following bilateral, focal lesions of the basal ganglia, with globus pallidus regions that connect with orbitofrontal (OFC) and ventromedial prefrontal cortex (VMPFC) particularly affected. Using two measures of oculomotor decision-making we show that apathy in this individual was associated with reward insensitivity. However, reward sensitivity could be established partially with levodopa and more effectively with a dopamine receptor agonist. Concomitantly, there was an improvement in the patients clinical state, with reduced apathy, greater motivation and increased social interactions. These findings provide a model system to study a key neuropsychiatric disorder. They demonstrate that reward insensitivity associated with basal ganglia dysfunction might be an important component of apathy that can be reversed by dopaminergic modulation.

Impulsivity and Rapid Decision-Making for Reward

Impulsivity is a feature of many brain disorders. Although often defined as the predisposition to act with an inadequate degree of deliberation, forethought, or control, it has proven difficult to measure. This may in part be due to the fact that it is a multifaceted construct, with impulsive decisions potentially arising as a result of a number of underlying mechanisms. Indeed, a “functional” degree of impulsivity may even promote effective behavior in healthy participants in a way that can be advantageous under certain circumstances. Although many tasks have been developed to study impulsivity, few examine decisions made rapidly, for time-sensitive rewards. In the current study we examine behavior in 59 adults on a manual “Traffic Light” task which requires participants to take risks under time pressure, if they are to maximize reward. We show that behavioral variables that index rapid anticipatory responding in this paradigm are correlated with one, specific self-report measure of impulsivity: “lack of premeditation” on the UPPS Impulsive Behavior Scale. Participants who scored more highly on this subscale performed better on the task. Moreover, anticipatory behavior reduced significantly with age (18–79 years), an effect that continued to be upheld after correction for potential age differences in the ability to judge the timing of responses. Based on these findings, we argue that the Traffic Light task provides a parametric method to study one aspect of impulsivity in health and disease: namely, rapid decision-making in pursuit of risky, time-sensitive rewards.

Sign language comprehension: Insights from misperceptions of different phonological parameters

Sign languages produced by Deaf people in everyday conversation differ in some interesting ways from spoken languages. Sign languages are perceived by the eyes and articulated through movements of the hands and the face, while spoken languages are perceived primarily by the ears and articulated through movements of the mouth and vocal tract. In spite of these fundamental differences in ‘signal properties’ the past 30 years of research on different sign languages has demonstrated that in several domains (e.g. comprehension, production and first language acquisition) there are remarkably similar patterns across the speech and sign modalities at both the behavioral and the neural level (Emmorey, 2002; MacSweeney et al., 2008). Through examinations of these similarities, and of differences between modalities, we are beginning to understand more about how sign languages and more generally the faculty of ‘language’ works. The question we ask in this chapter is this: What parts of the sign guide sign recognition in Deaf people looking at the signing stream? We know that vowels and consonants have different roles in speech recognition (van Ooijen, 1996), so it is possible that the main parameters of signs contribute in different ways to their recognition. This question relates to an emerging area of sign language linguistics, which looks at the parameters of signs and how they combine (i.e., the phonotactics of sign language), and at how parameters contribute to how signs are perceived and understood. In this chapter we first outline some of this related research. We then describe our research on segmentation in sign language. In particular, we describe our methods based on a sign-spotting task (derived from the word-spotting task as developed for spoken language by Cutler and Norris, 1988). Using the sign-spotting task, we tested the segmentation of real signs embedded in nonsense contexts

Standardization of Sign Languages.

Over the years attempts have been made to standardize sign languages. This form of language planning has been tackled by a variety of agents, most notably teachers of Deaf students, social workers, government agencies, and occasionally groups of Deaf people themselves. Their efforts have most often involved the development of sign language books with lists of signs in alphabetical order (as distinct from sign language principles) and more recently as CD-ROMs, DVDs, or websites. With regard to the all-important question about language standardization, Karin Hoyer asks, “Who is behind the effort?” and goes on to say that “standardization actions (often with the aim of reducing lexical variation) have frequently been undertaken with the strong support of the hearing-run education system—from outside, often without any support from the language users themselves” (2012, 32). Today, sign language planning is still carried out largely by hearing professionals; thus, that standardization still needs to be examined in relation to “language ownership” (Eichmann 2009).

Does reward modulate actions or bias attention

The neural mechanisms underlying decision making have often been probed by asking subjects to choose between movements (e.g., making a saccade to a left or right target) ([Sugrue et al., 2005][1]). In studying decisions, the influence of so-called “top-down” factors such as reward magnitude,

Experience from two decades of the Cambridge Rapid Access Neurology Clinic.

We report on the evolution of the rapid access neurology clinic (established in 1995) at Addenbrookes Hospital, Cambridge. Annualised attendance data demonstrate an ever increasing demand, with primary headache disorders now accounting for more than 40% of referrals. Secondary causes of headache (including intracranial tumours, idiopathic intracranial hypertension, carotid or vertebral artery dissection and subdural haematomas) remain infrequent. In all such cases, there were additional diagnostic clues. The number of patients referred with problems related to chronic neurological diseases has fallen considerably, reflecting the roles of specialist nurses and clinics. Imaging investigation of choice shifted from computerised tomography scan (45 to 16%) towards magnetic resonance imaging (17 to 47%). Management is increasingly on an outpatient basis, often without the need for a follow-up appointment. The experience presented here should inform further development of rapid access neurology clinics across the UK and suggests the need for acute headache services, in line with those for transient ischaemic attack and first seizure.

THE CHANGING FACE OF URGENT NEUROLOGY OUTPATIENT REFERRALS

Introduction A recent report published jointly by the RCP and ABN found that neurological presentations accounted for a significant proportion of GP and emergency room time, but access to acute neurological services was lacking. A study of urgent neurology outpatient referrals from primary health care physicians in Cambridge was first carried out in 1995 with the purpose of identifying which patients genuinely required urgent assessment, and the type of pathology seen. We thought it would be interesting to repeat this study a decade later to see whether there has been any change in the nature of neurological presentation, especially given recent changes in (for example) government health targets, waiting list initiatives, availability of imaging, and changes to local neurological services. Method Patients are referred to the neurology registrar on call, and they are booked in to the next available (weekday) emergency clinic slot. 458 patients were seen during 2008 and 2009, of which we had information for 415. Data was collected retrospectively from the original emergency clinic letter, follow up clinic letters, and investigation results. Results Seventy–five per cent of referrals were from general practitioners, most of which were within a 30 mile radius of Cambridge. Demand for an emergency clinic service has remained just as high, but there has been a clear change in presenting symptom and pathology seen, with more headaches (48%, compared to 27% in 1995), sensory limb disturbance (35% vs. 10%), and dizziness (19% vs. 5%). Conversely, fewer patients were seen with loss of consciousness (6% vs. 13%). 19% of patients were previously known to neurology, and of these 13% were patients with MS, compared to 42% in 1995. There were positive neurological examination findings in 60% of patients, the majority of which were focal cerebral. Only 7% of patients were admitted (compared to 19% in 1995), 52% were followed up in a neurology clinic, 12% were referred to a different specialty, and 32% were discharged. Following investigation, a definite ‘neurological’ diagnosis was made in 75% of patients, although this included headaches of all aetiologies (43% if excluded). Discussion There is still a clear need for an acute neurology clinic service given the high percentage of neurological diagnoses made. However, there is a clear change in pattern of presentation and diagnosis over the period 1995–2008. Far fewer patients were seen with loss of consciousness and MS relapses, a fact likely to be explained by the growth of other ‘rapid access’ services, such as a daily first seizure clinic and a nurse led community MS team. Just as many patients are being seen, and this may suggest that demand has grown to fill supply; referrals with more benign pathology have increased, in particular those for headache and dizziness. Emergency admission from the clinic is less common, and this may be due to improved availability of outpatient MRI and lumbar punctures in our programmed investigation unit, and also more structured outpatient pathways such as that for CNS tumours.

Energization and spoken language production: Evidence from progressive supranuclear palsy

ABSTRACT Energization is the process of initiating and sustaining a response over time. It has been described as one of three key “supervisory” attentional control processes associated with the frontal lobes. Attentional mechanisms, such as energization, are critical for a range of cognitive functions, such as spontaneous speech and other higher‐order tasks. We aimed to investigate the process of energization in a case series of patients with progressive supranuclear palsy (PSP). Patients with a diagnosis of PSP (N = 5), patient controls with a neurodegenerative condition (Alzheimers disease N = 3, frontotemporal dementia N = 2) and healthy older adult controls (N = 30) were assessed on a standard neuropsychological battery, including executive tasks and standard attention and language tests. Energization was investigated using word fluency tasks, samples of spontaneous speech and an experimental button‐pressing concentration task. Response rates for the word fluency, spontaneous speech and concentration tasks were separated into time periods, in order to compare response rates at different points across the tasks (e.g., first 15 s vs. last 45 s in a 60 s task). Four PSP patients showed a clear response pattern indicative of a decrease in energization. Healthy and patient controls remained consistent in their responding over time. Understanding how these underlying processes are impaired in PSP can ultimately inform intervention and management strategies, and has theoretical implications for models of spoken language production. HighlightsPatients with progressive supranuclear palsy are unable to maintain consistent responding.This pattern is characteristic of an energization impairment.Deficient energization observed on an experimental task, word fluency and in spontaneous speech.Energization plays a key role in the generation of ideas for spontaneous speech.

Endnote Remarks for TISLR12, Melbourne, Australia

Todays presentation is in three parts: first, to wrap up the conference, touching on the papers that I thought were of interest and some of the areas of research I feel would be worth developing; second, to mention some aspects of my own research; and finally to talk about some of the human rights implications of the work we do as sign language researchers.

Neurophysiological Features Of Hemiballism

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