Emily R. Murphy

Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement

Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats.

Persistent suppression of N‐methyl‐d‐aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that chronic NMDA receptor antagonism in animals may represent a useful model of neurobiological and related cognitive deficits in schizophrenia. Schizophrenia is associated with impairments in frontal lobe‐dependent cognitive functions, including working memory and attentional shifting. Deficits in attention and executive function have not been well characterized in animal models of schizophrenia using chronic NMDA receptor antagonist administration. We investigated whether subchronic systemic administration of the NMDA receptor antagonist phencyclidine (PCP) to rats followed by a drug washout period would produce enduring cognitive deficits on an attentional set‐shifting task. The task is functionally analogous to a sensitive test of frontal function in humans and non‐human primates. Subchronic PCP administration selectively impaired extradimensional shift learning without affecting other discrimination or reversal tasks. Moreover, acute treatment with the PDE10A inhibitor papaverine immediately prior to testing attenuated the PCP‐induced deficits in extradimensional shift learning across a range of doses. These data suggest that subchronic PCP administration may model effectively some of the cognitive deficits that are observed in schizophrenia, and that PDE10A inhibition may be an effective therapeutic route to improve executive function deficits associated with schizophrenia.

Opposing roles for 5-HT2A and 5-HT2C receptors in the nucleus accumbens on inhibitory response control in the 5-choice serial reaction time task.

Serotonin (5-HT) is thought to play an important role in the regulation of behavioral inhibition. Studies manipulating 5-HT function in the rodent brain indicate that 5-HT receptors regulate distinct forms of impulsive behavior, including impulsive responding in the 5-choice serial reaction time task (5CSRTT). The present study investigates the loci of effects mediated by 5-HT2A and 5-HT2C receptors in attention and inhibitory response control using microinfusions targeted at the nucleus accumbens (NAc), prelimbic cortex (PL) and infralimbic cortex (IL). Rats were implanted with bilateral guide cannulas and received infusions of the selective 5-HT2A receptor antagonist M100907 (0.1 and 0.3 μg) or selective 5-HT2C receptor antagonist SB242084 (0.1 and 0.5 μg) immediately prior to testing. The results show that intra-NAc infusions of M100907 significantly decrease impulsive responding on the 5CSRTT and at the highest dose increased omissions as well. By contrast, infusions of SB242084 into the NAc selectively and dose-dependently increased impulsivity. Neither M100907 nor SB242084 significantly altered impulsive responding following either intra-PL or intra-IL administration. However, SB242084 significantly decreased omissions following intra-PL administration (0.5 μg only). These data reveal opposing effects on impulsivity following 5-HT2A and 5-HT2C blockade in the NAc. Our results suggest that the NAc, but not the PL or IL, is implicated in the mediation of the effects of M100907 and SB242084 on inhibitory response control during baseline 5CSRTT performance.

Neuroimaging and Disorders of Consciousness: Envisioning an Ethical Research Agenda

The application of neuroimaging technology to the study of the injured brain has transformed how neuroscientists understand disorders of consciousness, such as the vegetative and minimally conscious states, and deepened our understanding of mechanisms of recovery. This scientific progress, and its potential clinical translation, provides an opportunity for ethical reflection. It was against this scientific backdrop that we convened a conference of leading investigators in neuroimaging, disorders of consciousness and neuroethics. Our goal was to develop an ethical frame to move these investigative techniques into mature clinical tools. This paper presents the recommendations and analysis of a Working Meeting on Ethics, Neuroimaging and Limited States of Consciousness held at Stanford University during June 2007. It represents an interdisciplinary approach to the challenges posed by the emerging use of neuroimaging technologies to describe and characterize disorders of consciousness.

Contrasting effects of selective lesions of nucleus accumbens core or shell on inhibitory control and amphetamine-induced impulsive behaviour

The core and shell subregions of the nucleus accumbens receive differential projections from areas of the medial prefrontal cortex that have dissociable effects on impulsive and perseverative responding. The contributions of these subregions to simple instrumental behaviour, inhibitory control and behavioural flexibility were investigated using a ‘forced choice’ task, various parameter manipulations and an omission schedule version of the task. Post‐training, selective core lesions were achieved with microinjections of quinolinic acid and shell lesions with ibotenic acid. After a series of behavioural task manipulations, rats were re‐stabilized on the standard version of the task and challenged with increasing doses of d‐amphetamine (vehicle, 0.5 or 1.0 mg/kg i.p. 30 min prior to test). Neither core‐ nor shell‐lesioned rats exhibited persistent deficits in simple instrumental behaviour or challenges to behavioural flexibility or inhibitory control. Significant differences between lesion groups were unmasked by d‐amphetamine challenge in the standard version of the forced task. Core lesions potentiated and shell lesions attenuated the dose‐dependent effect of d‐amphetamine on increasing anticipatory responses seen in sham rats. These data imply that the accumbens core and shell subregions do not play major roles in highly‐trained task performance or in challenges to behavioural control, but may have opposed effects following d‐amphetamine treatment. Specifically, they suggest the shell subregion to be necessary for dopaminergic activation driving amphetamine‐induced impulsive behaviour and the core subregion for the normal control of this behaviour via conditioned influences.

Brain Images as Legal Evidence

This paper explores whether brain images may be admitted as evidence in criminal trials under Federal Rule of Evidence 403, which weighs probative value against the danger of being prejudicial, confusing, or misleading to fact finders. The paper summarizes and evaluates recent empirical research relevant to these issues. We argue that currently the probative value of neuroimages for criminal responsibility is minimal, and there is some evidence of their potential to be prejudicial or misleading. We also propose experiments that will directly assess how jurors are influenced by brain images.

Misuse Made Plain: Evaluating Concerns About Neuroscience in National Security

Misuse Made Plain: Evaluating Concerns About Neuroscience in National Security Kelly Lowenberg a , Brenda M. Simon a , Amy Burns b , Libby Greismann c , Jennifer M. Halbleib b , Govind Persad b , David L.M. Preston c , Harker Rhodes b & Emily R. Murphy d a Stanford Law School Center for Law and the Biosciences , b Stanford Law School , c Stanford University , d Stanford Law School and Director of SIGNAL , Published online: 16 Apr 2010.

When scientific data become legal evidence.

In the 9 January issue, the News of the Week story “Brain scans of pain raise questions for the law” (G. Miller, p. [195][1]) and the Books review “Grappling with the gulf” (D. Greenbaum and M. Gerstein, p. [210][2]) highlight an important misunderstanding between lawyers and scientists

Chimeras of nurture.

The boy crouched in his room, rocking to and fro—like a beast in the Paris menagerie, the young doctor thought. He could not return his gaze, and his eyes wandered from one thing to the next, restl...