Is benzodiazepine-induced amnesia due to deactivation of the left prefrontal cortex?

Bagary, M.; Fluck, Emma; File, Sandra E.; Joyce, Eileen M.; Lockwood, G. G.; Grasby, Paul M.

doi:10.1007/s002130000419

Cited by 27 publications

(20 citation statements)

References 29 publications

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“…Thus, given the known role of the BG/DA system in reinforcement learning, and the converging results with Parkinson's disease patients (Frank et al, 2004), together with the arguments for preferential drug action in striatum described above, it should be relatively uncontroversial that the learning effects reported here stemmed from DA effects within the BG and these effects would be more difficult to explain with prefrontal mechanisms. This is further supported by our recent findings with the drug midazolam, which inactivates the PFC (and hippocampus) but leaves the striatum unaffected (e.g., Bagary et al, 2000;Reinsel et al, 2000). We found that whereas this drug profoundly impaired explicit memory processes, it spared probabilistic reinforcement learning (both positive and negative) and even enhanced some implicit forms of this learning (Frank, O'Reilly, & Curran, in press).…”

Section: Dopamine Effects In Prefrontal Cortex: D 1 and D 2 Receptorssupporting

confidence: 88%

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

Frank¹,

O’Reilly²

2006

Behavioral Neuroscience

430

490

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The authors test a neurocomputational model of dopamine function in cognition by administering to healthy participants low doses of D 2 agents cabergoline and haloperidol. The model suggests that DA dynamically modulates the balance of Go and No-Go basal ganglia pathways during cognitive learning and performance. Cabergoline impaired, while haloperidol enhanced, Go learning from positive reinforcement, consistent with presynaptic drug effects. Cabergoline also caused an overall bias toward Go responding, consistent with postsynaptic action. These same effects extended to working memory and attentional domains, supporting the idea that the basal ganglia/dopamine system modulates the updating of prefrontal representations. Drug effects interacted with baseline working memory span in all tasks. Taken together, the results support a unified account of the role of dopamine in modulating cognitive processes that depend on the basal ganglia.Keywords: basal ganglia, dopamine, cognition, computational, psychopharmacologyThe basal ganglia (BG) participate in various aspects of cognition and behavior by interacting with and modulating multiple areas of frontal cortex (Alexander, DeLong, & Strick, 1986). Similarly, the neurotransmitter dopamine (DA) plays a modulatory role in cognition through extensive diffuse projections from midbrain DA nuclei to the BG and frontal cortical areas (Fallon & Moore, 1978;Gerfen, 1992;Joel & Weiner, 2000). Several neurological conditions implicate DA dysfunction, including Parkinson's disease, attention deficit/hyperactivity disorder (ADHD), and schizophrenia (Abi-Dargham et al., 2000;Dougherty et al., 1999;Ilgin et al., 2001;Kish, Shannak, & Hornykiewicz, 1988;McGowan, Lawrence, Sales, Quested, & Graby, 2004;Nieoullon, 2002;Seeman, 1987;Weiner & Joel, 2002;Weinberger, 1987). Notably, the cognitive deficits observed in all of these conditions are qualitatively similar to those observed in patients with damage to prefrontal cortex (PFC; Barch et al., 2001;Brown & Marsden, 1990;Cools, Barker, Sahakian, & Robbins, 2001;Perlstein, Dixit, Carter, Noll, & Cohen, 2003;Willcutt et al., 2005). Consequently, the overwhelming tendency in the literature is to attribute patient cognitive deficits to dopaminergic dysfunction within PFC. This is a potentially valid attribution, given that selective disruption to prefrontal DA in monkeys gives rise to cognitive deficits that are similar to those observed under full excitotoxic PFC lesions (Sawaguchi & Goldman-Rakic, 1991; Williams & GoldmanRakic, 1995). However, there is growing evidence in both animals and humans that DA dysfunction within the BG alone can lead to frontal-like cognitive deficits (Collins, Wilkinson, Everitt, Robbins, & Roberts, 2000;Crofts et al., 2001;Frank, 2005;J. O. Rinne et al., 2000).Psychopharmacological studies that transiently manipulate the DA system in healthy individuals can potentially inform the cause of DA-related cognitive deficits. In particular, drugs that target the D 2 receptor, which is predominantly expressed in BG re...

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Section: Dopamine Effects In Prefrontal Cortex: D 1 and D 2 Receptorssupporting

confidence: 88%

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

Frank¹,

O’Reilly²

2006

Behavioral Neuroscience

430

490

View full text Add to dashboard Cite

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“…Specifically, these competitive dynamics serve to sharpen cognitive representations by amplifying activity in the most active, task-relevant, representations (e.g., the most appropriate word to complete a sentence) and suppressing competing representations (e.g., for the many other word possibilities). A tenet of the model is that these critical dynamics occur via inhibitory, GABAergic interneurons (12)(13)(14). Here we test the predictions of the model regarding selection processes that are supported by the left ventrolateral prefrontal cortex.…”

mentioning

confidence: 94%

Neural inhibition enables selection during language processing

Snyder

Hutchison²,

Nyhus³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

133

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Whether grocery shopping or choosing words to express a thought, selecting between options can be challenging, especially for people with anxiety. We investigate the neural mechanisms supporting selection during language processing and its breakdown in anxiety.Our neural network simulations demonstrate a critical role for competitive, inhibitory dynamics supported by GABAergic interneurons. As predicted by our model, we find that anxiety (associated with reduced neural inhibition) impairs selection among options and associated prefrontal cortical activity, even in a simple, nonaffective verb-generation task, and the GABA agonist midazolam (which increases neural inhibition) improves selection, whereas retrieval from semantic memory is unaffected when selection demands are low. Neural inhibition is key to choosing our words.P eople claim to love the freedom of unlimited choices, but in reality we are often stymied by too many options and disconcerted by not knowing what the outcomes of our choices will be. Selecting among multiple options is effortful and time consuming, whether choosing among fruit jams (1), retirement plans (2), or medical treatments (3). This problem is particularly pervasive during language production, when we must constantly choose words to express a thought (4-6). People with anxiety disorders find coping with too many options particularly difficult, and struggle with decision-making problems (7), indecisiveness (8), and intolerance of uncertainty (9). What mechanisms allow us to select among multiple options when speaking, and why does this process break down in people with anxiety? Current psychological theories of selection focus on the importance of cognitive control (5) and prefrontal cortical regions (4, 6, 10), but do not address questions at the level of specific neural mechanisms. We address these questions by implementing a unified, biologically plausible computational model of selection, and testing its predictions about both brain and behavior in humans making choices in a well-controlled language production task.Our model demonstrates how competitive, inhibitory dynamics among neurons in prefrontal cortical networks (11) support selection between alternatives. Specifically, these competitive dynamics serve to sharpen cognitive representations by amplifying activity in the most active, task-relevant, representations (e.g., the most appropriate word to complete a sentence) and suppressing competing representations (e.g., for the many other word possibilities). A tenet of the model is that these critical dynamics occur via inhibitory, GABAergic interneurons (12-14). Here we test the predictions of the model regarding selection processes that are supported by the left ventrolateral prefrontal cortex. We do so for the following reasons: (i) this region has been implicated in selecting among competing alternatives during language processing (6, 15-18); (ii) this region shows altered activity in individuals who suffer from anxiety (particularly anxious apprehension, characterized by w...

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Section: It Is Well Documented That Acute Administration Of the Benzomentioning

confidence: 99%

“…Although the generalizability of these results to other measures of executive function may be questioned, this study provides strong evidence that different effects of benzodiazepines can be dissociated using PET. Bagary et al (2000) recently reported results of a placebo-controlled 746 M.Z. Mintzer et al N EUROPSYCHOPHARMACOLOGY 2001 -VOL .…”

Section: It Is Well Documented That Acute Administration Of the Benzomentioning

confidence: 99%

“…The results revealed significant deactivation in the midazolam condition during episodic memory encoding in the calcarine sulci bilaterally (BA 17), but not in the prefrontal cortex. An account of the differences between the Coull et al (1999) and Bagary et al (2000) studies in regions showing benzodiazepineinduced deactivation during encoding is not readily apparent, but may be related to methodological differences between the studies, such as the modality of stimulus presentation (i.e., visual vs. auditory) and the nature of the control task to which the encoding task was compared.The present PET study was designed to examine effects of the benzodiazepine hypnotic triazolam (Halcion®) on rCBF during episodic memory encoding. Both the Coull et al (1999) and Bagary et al (2000) studies utilized a mixed design in which the primary comparisons were made between rCBF during performance of tasks presented before versus after drug administration within a single session, and drug condition (drug versus placebo) was manipulated between subjects; the purpose of the placebo condition was to control for confounding effects of time within the session.…”

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confidence: 99%

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Effects of Triazolam on Brain Activity During Episodic Memory Encoding: A PET Study

Mintzer

Griffiths

Contoreggi

et al. 2001

Neuropsychopharmacology

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It is well documented that acute administration of the benzodiazepine hypnotic drug triazolam (Halcion®) impairs episodic memory encoding. We examined the neuroanatomical substrates of this effect in healthy adult volunteers using a double-blind, within-subject design. Following oral capsule administration (0.25 mg/70 kg triazolam or placebo), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) withBenzodiazepine anxiolytic/hypnotic drugs, such as diazepam (Valium®), alprazolam (Xanax®), lorazepam (Ativan®), and triazolam (Halcion®), are among the most widely prescribed psychotropic medications. In addition to their anxiolytic and sedative properties, benzodiazepines also have memory-and cognitiveimpairing effects (for reviews see Curran 1991;Duka et al. 1996;Polster 1993). Acute benzodiazepine administration produces dose-related decrements in episodic memory encoding, while leaving retrieval of previously encoded material intact. Episodic memory refers to conscious long-term memory for a personally experienced event that is associated with a specific spatial and temporal context (Tulving 1972(Tulving , 1983. Encoding refers to the cognitive processes engaged (either intentionally or unintentionally) during the initial event that lead to the creation of a representation or trace of the event in epi- N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 5 Triazolam and PET 745 sodic memory. Thus, if information is presented for study while a participant is under the influence of a benzodiazepine, subsequent memory for that information is impaired, even when memory testing occurs while the drug is no longer in the system; however, if information presented before drug administration is tested under the influence of a benzodiazepine, no impairment is observed. Benzodiazepines act at specific receptor sites on the gamma-aminobutyric acid (GABA) A receptor complex by facilitating the action of GABA, the primary inhibitory neurotransmitter in the central nervous system (CNS) (Mohler and Okada 1977;Squires and Braestrup 1977). Benzodiazepine receptors are distributed widely throughout the brain, and, therefore, the initial sites of benzodiazepine action in the brain are known (Fernandez-Lopez et al. 1997;Frey et al. 1996;Millet et al. 2000;Persson et al. 1985). Nonetheless, little is known about the brain circuitry affected by benzodiazepine administration during episodic memory encoding, because the distribution of such effects likely goes beyond the sites of initial receptor interactions.Over the past decade, considerable progress has been made in identifying the brain regions involved in episodic memory encoding under nonpharmacological conditions using noninvasive functional neuroimaging techniques, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), which enable measurement of brain activity in vivo while a human subject performs specific tasks. Encoding has been investigated most commonly by comparing brain activity associated with a cond...

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Is benzodiazepine-induced amnesia due to deactivation of the left prefrontal cortex?

Abstract: These results suggest that a specific interaction with prefrontal cortex activation does not underlie the amnesic effect of midazolam. However, it remains possible that a threshold level of prefrontal rCBF is necessary for encoding and that, after midazolam, this was not reached.

Cited by 27 publications

References 29 publications

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

Neural inhibition enables selection during language processing

Effects of Triazolam on Brain Activity During Episodic Memory Encoding: A PET Study

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