Publications by authors named "Laith Alexander"

12 Publications

  • Page 1 of 1

The anterior cingulate cortex as a key locus of ketamine's antidepressant action.

Neurosci Biobehav Rev 2021 May 11;127:531-554. Epub 2021 May 11.

Department of Psychological Medicine, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; South London and Maudsley NHS Foundation Trust, London, United Kingdom.

The subdivisions of the anterior cingulate cortex (ACC) - including subgenual, perigenual and dorsal zones - are implicated in the etiology, pathogenesis and treatment of major depression. We review an emerging body of evidence which suggests that changes in ACC activity are critically important in mediating the antidepressant effects of ketamine, the prototypical member of an emerging class of rapidly acting antidepressants. Infusions of ketamine induce acute (over minutes) and post-acute (over hours to days) modulations in subgenual and perigenual activity, and importantly, these changes can correlate with antidepressant efficacy. The subgenual and dorsal zones of the ACC have been specifically implicated in ketamine's anti-anhedonic effects. We emphasize the synergistic relationship between neuroimaging studies in humans and brain manipulations in animals to understand the causal relationship between changes in brain activity and therapeutic efficacy. We conclude with circuit-based perspectives on ketamine's action: first, related to ACC function in a central network mediating affective pain, and second, related to its role as the anterior node of the default mode network.
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http://dx.doi.org/10.1016/j.neubiorev.2021.05.003DOI Listing
May 2021

Quantifying anhedonia-like symptoms in marmosets using appetitive Pavlovian conditioning.

STAR Protoc 2021 Jun 17;2(2):100454. Epub 2021 Apr 17.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.

Blunted reward responsivity is associated with anhedonia in humans and is a core feature of depression. This protocol describes how to train the common marmoset, , on an appetitive Pavlovian conditioning paradigm to measure behavioral and cardiovascular correlates of anticipatory and consummatory phases of reward processing. We describe how to use intracerebral infusions to manipulate brain regions whose activity is relevant to impaired reward processing in depression and how the paradigm can be used to test antidepressant efficacy. For complete details on the use and execution of this protocol, please refer to Alexander et al. (2019).
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http://dx.doi.org/10.1016/j.xpro.2021.100454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082163PMC
June 2021

COVIDReady2 study protocol: cross-sectional survey of medical student volunteering and education during the COVID-19 pandemic in the United Kingdom.

BMC Med Educ 2021 Apr 14;21(1):211. Epub 2021 Apr 14.

Nuffield Department of Primary Care Health Sciences, Medical Sciences Division, University of Oxford, Oxford, UK.

Background: The coronavirus disease 2019 pandemic has led to global disruption of healthcare. Many students volunteered to provide clinical support. Volunteering to work in a clinical capacity was a unique medical education opportunity; however, it is unknown whether this was a positive learning experience or which volunteering roles were of most benefit to students.

Methods: The COVIDReady2 study is a national cross-sectional study of all medical students at medical schools in the United Kingdom. The primary outcome is to explore the experiences of medical students who volunteered during the pandemic in comparison to those who did not. We will compare responses to determine the educational benefit and issues they faced. In addition to quantitative analysis, thematic analysis will be used to identify themes in qualitative responses.

Discussion: There is a growing body of evidence to suggest that service roles have potential to enhance medical education; yet, there is a shortage of studies able to offer practical advice for how these roles may be incorporated in future medical education. We anticipate that this study will help to identify volunteer structures that have been beneficial for students, so that similar infrastructures can be used in the future, and help inform medical education in a non-pandemic setting.

Trial Registration: Not Applicable.
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http://dx.doi.org/10.1186/s12909-021-02629-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045566PMC
April 2021

Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat.

Nat Commun 2020 10 26;11(1):5386. Epub 2020 Oct 26.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3DY, UK.

Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat. F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threat contrary to the beneficial effects we have previously demonstrated on over-activation induced reward blunting, illustrating the symptom-specificity of its actions.
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http://dx.doi.org/10.1038/s41467-020-19167-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588412PMC
October 2020

Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset.

Proc Natl Acad Sci U S A 2020 10 21;117(40):25116-25127. Epub 2020 Sep 21.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom;

The ventromedial prefrontal cortex (vmPFC) is a key brain structure implicated in mood and anxiety disorders, based primarily on evidence from correlational neuroimaging studies. Composed of a number of brain regions with distinct architecture and connectivity, dissecting its functional heterogeneity will provide key insights into the symptomatology of these disorders. Focusing on area 14, lying on the medial and orbital surfaces of the gyrus rectus, this study addresses a key question of causality. Do changes in area 14 activity induce changes in threat- and reward-elicited responses within the nonhuman primate, the common marmoset, similar to that seen in mood and anxiety disorders? Area 14 overactivation was found to induce heightened responsivity to uncertain, low-imminence threat while blunting cardiovascular and behavioral anticipatory arousal to high-value food reward. Conversely, inactivation enhanced the arousal to high-value reward cues while dampening the acquisition of cardiovascular and behavioral responses to a Pavlovian threat cue. Basal cardiovascular activity, including heart rate variability and sympathovagal balance, which are dysfunctional in mood and anxiety disorders, are insensitive to alterations in area 14 activity as is the extinction of conditioned threat responses. The distinct pattern of dysregulation compared to neighboring region area 25 highlights the heterogeneity of function within vmPFC and reveals how the effects of area 14 overactivation on positive and negative reactivity mirror symptoms of anhedonia and anxiety that are so often comorbid in mood disorders.
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http://dx.doi.org/10.1073/pnas.2009657117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547281PMC
October 2020

How can I get involved in research as a medical student?

Authors:
Laith Alexander

BMJ 2020 08 26;370:m2586. Epub 2020 Aug 26.

St Thomas' Hospital, London, UK.

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http://dx.doi.org/10.1136/bmj.m2586DOI Listing
August 2020

Life, learning, and medicine: advice to new medical students from a junior doctor.

Authors:
Laith Alexander

BMJ 2020 08 21;370:m2165. Epub 2020 Aug 21.

St Thomas' Hospital, London, UK.

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http://dx.doi.org/10.1136/bmj.m2165DOI Listing
August 2020

Lade Oyeyinka is a sexual health nurse.

Authors:
Laith Alexander

BMJ 2020 08 18;370:m2447. Epub 2020 Aug 18.

St Thomas' Hospital, London, UK.

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http://dx.doi.org/10.1136/bmj.m2447DOI Listing
August 2020

A Focus on the Functions of Area 25.

Brain Sci 2019 Jun 3;9(6). Epub 2019 Jun 3.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.

Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but activity in this area is emerging as a crucial correlate of mood and affective disorder symptomatology. The cortical and subcortical connectivity of area 25 suggests it may act as an interface between the bioregulatory and emotional states that are aberrant in disorders such as depression. However, evidence for such a role is limited because of uncertainty over the functional homologue of area 25 in rodents, which hinders cross-species translation. This emphasizes the need for causal manipulations in monkeys in which area 25, and the prefrontal and cingulate regions in which it is embedded, resemble those of humans more than rodents. In this review, we consider physiological and behavioral evidence from non-pathological and pathological studies in humans and from manipulations of area 25 in monkeys and its putative homologue, the infralimbic cortex (IL), in rodents. We highlight the similarities between area 25 function in monkeys and IL function in rodents with respect to the regulation of reward-driven responses, but also the apparent inconsistencies in the regulation of threat responses, not only between the rodent and monkey literatures, but also within the rodent literature. Overall, we provide evidence for a causal role of area 25 in both the enhanced negative affect and decreased positive affect that is characteristic of affective disorders, and the cardiovascular and endocrine perturbations that accompany these mood changes. We end with a brief consideration of how future studies should be tailored to best translate these findings into the clinic.
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http://dx.doi.org/10.3390/brainsci9060129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627335PMC
June 2019

Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25 to Regulate the Behavioral and Cardiovascular Correlates of High-Trait Anxiety.

J Neurosci 2019 04 4;39(16):3094-3107. Epub 2019 Feb 4.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,

High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studies of high-trait anxiety reveals dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp) and rodent studies reveal the importance of aHipp glutamatergic hypofunction, the causal involvement of aHipp glutamate and its interaction with these areas in the primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety. High-trait anxiety predisposes sufferers to the development of anxiety and depression. Although neuroimaging of these disorders and rodent modeling implicate dysregulation in hippocampal glutamate and the subgenual/perigenual cingulate cortices (areas 25/32), the causal involvement of these structures in endogenous high-trait anxiety and their interaction are unknown. Here, we demonstrate that increased trait anxiety in marmoset monkeys correlates with reduced hippocampal glutamate and that increasing hippocampal glutamate release in high-trait-anxious monkeys normalizes the aberrant behavioral and cardiovascular responsivity to potential threats. This normalization was blocked by simultaneous inactivation of area 25, but not area 32. These findings provide casual evidence in primates that hippocampal glutamatergic hypofunction regulates endogenous high-trait anxiety and the hippocampal-area 25 circuit is a potential therapeutic target.
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http://dx.doi.org/10.1523/JNEUROSCI.2451-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468106PMC
April 2019

Fractionating Blunted Reward Processing Characteristic of Anhedonia by Over-Activating Primate Subgenual Anterior Cingulate Cortex.

Neuron 2019 01 4;101(2):307-320.e6. Epub 2018 Dec 4.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK. Electronic address:

Anhedonia is a core symptom of depression, but the underlying neurobiological mechanisms are unknown. Correlative neuroimaging studies implicate dysfunction within ventromedial prefrontal cortex, but the causal roles of specific subregions remain unidentified. We addressed these issues by combining intracerebral microinfusions with cardiovascular and behavioral monitoring in marmoset monkeys to show that over-activation of primate subgenual anterior cingulate cortex (sgACC, area 25) blunts appetitive anticipatory, but not consummatory, arousal, whereas manipulations of adjacent perigenual ACC (pgACC, area 32) have no effect. sgACC/25 over-activation also reduces the willingness to work for reward. F-FDG PET imaging reveals over-activation induced metabolic changes in circuits involved in reward processing and interoception. Ketamine treatment ameliorates the blunted anticipatory arousal and reverses associated metabolic changes. These results demonstrate a causal role for primate sgACC/25 over-activity in selective aspects of impaired reward processing translationally relevant to anhedonia, and ketamine's modulation of an affective network to exert its action.
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http://dx.doi.org/10.1016/j.neuron.2018.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344231PMC
January 2019

Opposing roles of primate areas 25 and 32 and their putative rodent homologs in the regulation of negative emotion.

Proc Natl Acad Sci U S A 2017 05 1;114(20):E4075-E4084. Epub 2017 May 1.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom;

Disorders of dysregulated negative emotion such as depression and anxiety also feature increased cardiovascular mortality and decreased heart-rate variability (HRV). These disorders are correlated with dysfunction within areas 25 and 32 of the ventromedial prefrontal cortex (vmPFC), but a causal relationship between dysregulation of these areas and such symptoms has not been demonstrated. Furthermore, cross-species translation is limited by inconsistent findings between rodent fear extinction and human neuroimaging studies of negative emotion. To reconcile these literatures, we applied an investigative approach to the brain-body interactions at the core of negative emotional dysregulation. We show that, in marmoset monkeys (a nonhuman primate that has far greater vmPFC homology to humans than rodents), areas 25 and 32 have causal yet opposing roles in regulating the cardiovascular and behavioral correlates of negative emotion. In novel Pavlovian fear conditioning and extinction paradigms, pharmacological inactivation of area 25 decreased the autonomic and behavioral correlates of negative emotion expectation, whereas inactivation of area 32 increased them via generalization. Area 25 inactivation also increased resting HRV. These findings are inconsistent with current theories of rodent/primate prefrontal functional similarity, and provide insight into the role of these brain regions in affective disorders. They demonstrate that area 32 hypoactivity causes behavioral generalization relevant to anxiety, and that area 25 is a causal node governing the emotional and cardiovascular symptomatology relevant to anxiety and depression.
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http://dx.doi.org/10.1073/pnas.1620115114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441783PMC
May 2017