Mechanisms Underlying Motivational Dysfunction in Schizophrenia

Negative symptoms are a debilitating feature of schizophrenia which are often resistant to pharmacological intervention. The mechanisms underlying them remain poorly understood, and diagnostic methods rely on phenotyping through validated questionnaires. Deeper endo-phenotyping is likely to be necessary in order to improve current understanding. In the last decade, valuable behavioural insights have been gained through the use of effort-based decision making (EBDM) tasks. These have highlighted impairments in reward-related processing in schizophrenia, particularly associated with negative symptom severity. Neuroimaging investigations have related these changes to dysfunction within specific brain networks including the ventral striatum (VS) and frontal brain regions. Here, we review the behavioural and neural evidence associated with negative symptoms, shedding light on potential underlying mechanisms and future therapeutic possibilities. Findings in the literature suggest that schizophrenia is characterised by impaired reward based learning and action selection, despite preserved hedonic responses. Associations between amotivation and reward-processing deficits have not always been clear, and may be mediated by factors including cognitive dysfunction or dysfunctional or self-defeatist beliefs. Successful endo-phenotyping of negative symptoms as a function of objective behavioural and neural measurements is crucial in advancing our understanding of this complex syndrome. Additionally, transdiagnostic research–leveraging findings from other brain disorders, including neurological ones–can shed valuable light on the possible common origins of motivation disorders across diseases and has important implications for future treatment development.

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Epigenetic Regulatory Dynamics in Models of Methamphetamine-Use Disorder

Genes ◽

10.3390/genes12101614 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1614

Author(s):

Subramaniam Jayanthi ◽

Michael T. McCoy ◽

Jean Lud Cadet

Keyword(s):

Gene Expression ◽

Brain Regions ◽

Reward Processing ◽

Post Translational Modifications ◽

Methamphetamine Use ◽

Underlying Mechanisms ◽

Induced Changes ◽

Methamphetamine Use Disorder ◽

Disease Exposure

Methamphetamine (METH)-use disorder (MUD) is a very serious, potentially lethal, biopsychosocial disease. Exposure to METH causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug-seeking and drug-taking behavior that can remain a lifelong struggle. It is crucial to elucidate underlying mechanisms by which exposure to METH leads to molecular neuroadaptive changes at transcriptional and translational levels. Changes in gene expression are controlled by post-translational modifications via chromatin remodeling. This review article focuses on the brain-region specific combinatorial or distinct epigenetic modifications that lead to METH-induced changes in gene expression.

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Exploring the dog–human relationship by combining fMRI, eye-tracking and behavioural measures

Scientific Reports ◽

10.1038/s41598-020-79247-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sabrina Karl ◽

Magdalena Boch ◽

Anna Zamansky ◽

Dirk van der Linden ◽

Isabella C. Wagner ◽

...

Keyword(s):

Eye Tracking ◽

Preference Test ◽

Brain Regions ◽

Reward Processing ◽

Human Relationship ◽

Motor Processing ◽

Multi Method Approach ◽

Underlying Mechanisms ◽

Human Faces ◽

Familiar Person

AbstractBehavioural studies revealed that the dog–human relationship resembles the human mother–child bond, but the underlying mechanisms remain unclear. Here, we report the results of a multi-method approach combining fMRI (N = 17), eye-tracking (N = 15), and behavioural preference tests (N = 24) to explore the engagement of an attachment-like system in dogs seeing human faces. We presented morph videos of the caregiver, a familiar person, and a stranger showing either happy or angry facial expressions. Regardless of emotion, viewing the caregiver activated brain regions associated with emotion and attachment processing in humans. In contrast, the stranger elicited activation mainly in brain regions related to visual and motor processing, and the familiar person relatively weak activations overall. While the majority of happy stimuli led to increased activation of the caudate nucleus associated with reward processing, angry stimuli led to activations in limbic regions. Both the eye-tracking and preference test data supported the superior role of the caregiver’s face and were in line with the findings from the fMRI experiment. While preliminary, these findings indicate that cutting across different levels, from brain to behaviour, can provide novel and converging insights into the engagement of the putative attachment system when dogs interact with humans.

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O5.5. THE NEUROBIOLOGY OF NEGATIVE SYMPTOMS IN SCHIZOPHRENIA: MULTI-MODAL PET AND FMRI FINDINGS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa028.028 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S12-S13

Author(s):

Oliver Howes ◽

Abhishekh Ashok ◽

Ekaterina Shatalina ◽

Eugenii Rabiner ◽

Tiago Reis Marques

Keyword(s):

Opioid Receptor ◽

Negative Symptoms ◽

Brain Regions ◽

Brain Network ◽

Mu Opioid Receptor ◽

Reward Processing ◽

Neural Activation ◽

Mu Opioid ◽

Reward Anticipation

Abstract Background The neurobiological mechanisms underlying anhedonia and other negative symptoms in schizophrenia are unknown. Understanding this would help identify treatments for these symptoms. Pre-clinical and human evidence shows the mu-opioid receptor plays a key role in reward processing and anhedonia. However, the contribution of Mu Opioid Receptor (MOR) signalling to negative symptoms and the reward processing abnormalities in schizophrenia is unknown. Here, we investigated for the first time in vivo in patients whether MOR availability is altered in schizophrenia and if this is associated with the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging. Methods Forty volunteers (n=20 patients with schizophrenia and 20 age and sex-matched healthy controls) received an [11C]-carfentanil PET scan to measure MOR availability, a structural MRI scan and a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. All the patients met criteria for persistent negative symptoms. Our primary ROI for the PET analysis was the striatum. In addition, we analysed MOR availability in brain regions in the hedonic network (the striatum, insula and anterior cingulate cortex). The fMRI analysis focused on brain regions in this hedonic network as these have previously associated with MOR mediated reward processing in humans and preclinical studies. Brain volumes of regions of interest (ROIs) were also extracted. Results The analysis showed significantly lower MOR availability in the striatum of patients with schizophrenia relative to controls (patients vs. controls (mean binding potential (BPND) ± SEM): 1.54 ± 0.06 vs. 1.7 ± 0.05, Cohen’s d= 0.7, t=-2.2, df (37), p<0.05). There was also a significant effect of both group (F (5, 222) = 334.5, p<0.05) and ROI (F (1, 222) = 5.65, p<0.05) on BPND measures in the hedonic brain network. The group* ROI interaction was not significant (F (5, 222) = 0.2167, p>0.05). There were no significant differences in the volume of the striatum or other brain regions between groups (patients vs controls: mean ± SEM (mm3) 13019 ± 302 vs 12937 ± 327 respectively, p = 0.86). Reward anticipation in controls was associated with increased neural activation in a widespread network of brain regions including the ventral striatum and insula. The activation in the ventral striatum was significantly lower in patients compared to healthy controls. MOR availability was positively correlated with neural activation in the insula during reward anticipation in controls (spearman’s rho=0.6, p=0.006) but not in patients (spearman’s rho=0.13, p=0.57). In contrast, MOR availability in the striatum was not associated with neural activation in the striatum. Discussion These data show for the first time in vivo that mu-opioid receptor availability is lower in schizophrenia across the hedonic brain network. Moreover, patients with schizophrenia show altered coupling between mu-opioid signalling in the insula and brain activation during reward anticipation. These findings identify the mu-opioid receptor as a potential therapeutic target for reward dysfunction in schizophrenia.

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Conceptual disorganization and redistribution of resting state cortical hubs in untreated first episode psychosis: A 7T MRI study

10.31234/osf.io/rzvby ◽

2020 ◽

Author(s):

Avyarthana Dey ◽

Kara Dempster ◽

Michael Mackinley ◽

Peter Jeon ◽

Tushar Das ◽

...

Keyword(s):

Negative Symptoms ◽

Superior Temporal Gyrus ◽

Brain Regions ◽

First Episode Psychosis ◽

Cortical Reorganization ◽

First Episode ◽

Formal Thought Disorder ◽

Whole Brain ◽

Episode Psychosis ◽

Positive And Negative Symptoms

Background:Network level dysconnectivity has been studied in positive and negative symptoms of schizophrenia. Conceptual disorganization (CD) is a symptom subtype which predicts impaired real-world functioning in psychosis. Systematic reviews have reported aberrant connectivity in formal thought disorder, a construct related to CD. However, no studies have investigated whole-brain functional correlates of CD in psychosis. We sought to investigate brain regions explaining the severity of CD in patients with first-episode psychosis (FEPs) compared with healthy controls (HCs).Methods:We computed whole-brain binarized degree centrality maps of 31 FEPs, 25 HCs and characterized the patterns of network connectivity in the two groups. In FEPs, we related these findings to the severity of CD. We also studied the effect of positive and negative symptoms on altered network connectivity.Results:Compared to HCs, reduced hubness of a right superior temporal gyrus (rSTG) cluster was observed in the FEPs. In patients exhibiting high CD, increased hubness of a medial superior parietal (mSPL) cluster was observed, compared to patients exhibiting low CD. These two regions were strongly correlated with CD scores but not with other symptom scores.Discussion:Our observations are congruent with previous findings of reduced but not increased hubness. We observed increased hubness of mSPL suggesting that cortical reorganization occurs to provide alternate routes for information transfer.Conclusion:These findings provide insight into the underlying neural processes mediating the presentation of symptoms in untreated FEP. A longitudinal tracking of the symptom course will be useful to assess the mechanisms underlying these compensatory changes.

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Antagonism between brain regions relevant for cognitive control and emotional memory facilitates the generation of humorous ideas

Scientific Reports ◽

10.1038/s41598-021-89843-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Florian Bitsch ◽

Philipp Berger ◽

Andreas Fink ◽

Arne Nagels ◽

Benjamin Straube ◽

...

Keyword(s):

Cognitive Control ◽

Positive Emotions ◽

Emotional Memory ◽

Brain Regions ◽

Neural Mechanisms ◽

Functional Magnetic Resonance ◽

Frontal Brain ◽

Successful Resolution ◽

Neural Underpinnings ◽

The Brain

AbstractThe ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the hypoactivation of frontal brain regions is associated with an hyperactivation in the amygdala and vice versa. This antagonistic connectivity is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.

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Avolition as the core negative symptom in schizophrenia: relevance to pharmacological treatment development

npj Schizophrenia ◽

10.1038/s41537-021-00145-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Gregory P. Strauss ◽

Lisa A. Bartolomeo ◽

Philip D. Harvey

Keyword(s):

Negative Symptom ◽

Negative Symptoms ◽

Clinical Trial Design ◽

Core Component ◽

Treatment Target ◽

Global Improvement ◽

Treatment Development ◽

The Core ◽

Current Review ◽

Symptom Domains

AbstractNegative symptoms have long been considered a core component of schizophrenia. Modern conceptualizations of the structure of negative symptoms posit that there are at least two broad dimensions (motivation and pleasure and diminished expression) or perhaps five separable domains (avolition, anhedonia, asociality, blunted affect, alogia). The current review synthesizes a body of emerging research indicating that avolition may have a special place among these dimensions, as it is generally associated with poorer outcomes and may have distinct neurobiological mechanisms. Network analytic findings also indicate that avolition is highly central and interconnected with the other negative symptom domains in schizophrenia, and successfully remediating avolition results in global improvement in the entire constellation of negative symptoms. Avolition may therefore reflect the most critical treatment target within the negative symptom construct. Implications for targeted treatment development and clinical trial design are discussed.

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Conscious perception and perceptual echoes: a binocular rivalry study

Neuroscience of Consciousness ◽

10.1093/nc/niab007 ◽

2021 ◽

Vol 2021 (1) ◽

Author(s):

Canhuang Luo ◽

Rufin VanRullen ◽

Andrea Alamia

Keyword(s):

Binocular Rivalry ◽

Visual Information ◽

Visual Stimulation ◽

Brain Regions ◽

Travelling Wave ◽

Alpha Power ◽

Conscious Perception ◽

Impulse Response Functions ◽

Band Frequency ◽

Underlying Mechanisms

Abstract Alpha rhythms (∼10Hz) in the human brain are classically associated with idling activities, being predominantly observed during quiet restfulness with closed eyes. However, recent studies demonstrated that alpha (∼10Hz) rhythms can directly relate to visual stimulation, resulting in oscillations, which can last for as long as one second. This alpha reverberation, dubbed perceptual echoes (PE), suggests that the visual system actively samples and processes visual information within the alpha-band frequency. Although PE have been linked to various visual functions, their underlying mechanisms and functional role are not completely understood. In this study, we investigated the relationship between conscious perception and the generation and the amplitude of PE. Specifically, we displayed two coloured Gabor patches with different orientations on opposite sides of the screen, and using a set of dichoptic mirrors, we induced a binocular rivalry between the two stimuli. We asked participants to continuously report which one of two Gabor patches they consciously perceived, while recording their EEG signals. Importantly, the luminance of each patch fluctuated randomly over time, generating random sequences from which we estimated two impulse-response functions (IRFs) reflecting the PE generated by the perceived (dominant) and non-perceived (suppressed) stimulus, respectively. We found that the alpha power of the PE generated by the consciously perceived stimulus was comparable with that of the PE generated during monocular vision (control condition) and higher than the PE induced by the suppressed stimulus. Moreover, confirming previous findings, we found that all PEs propagated as a travelling wave from posterior to frontal brain regions, irrespective of conscious perception. All in all our results demonstrate a correlation between conscious perception and PE, suggesting that the synchronization of neural activity plays an important role in visual sampling and conscious perception.

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Neural substrates of propranolol-induced impairments in the reconsolidation of nicotine-associated memories in smokers

Translational Psychiatry ◽

10.1038/s41398-021-01566-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiao Lin ◽

Jiahui Deng ◽

Kai Yuan ◽

Qiandong Wang ◽

Lin Liu ◽

...

Keyword(s):

Neural Activity ◽

Neural Substrates ◽

Brain Regions ◽

Reward Processing ◽

Memory Reconsolidation ◽

Functional Magnetic Resonance ◽

Resonance Imaging ◽

Postcentral Gyrus ◽

Propranolol Group ◽

Propranolol Administration

AbstractThe majority of smokers relapse even after successfully quitting because of the craving to smoking after unexpectedly re-exposed to smoking-related cues. This conditioned craving is mediated by reward memories that are frequently experienced and stubbornly resistant to treatment. Reconsolidation theory posits that well-consolidated memories are destabilized after retrieval, and this process renders memories labile and vulnerable to amnestic intervention. This study tests the retrieval reconsolidation procedure to decrease nicotine craving among people who smoke. In this study, 52 male smokers received a single dose of propranolol (n = 27) or placebo (n = 25) before the reactivation of nicotine-associated memories to impair the reconsolidation process. Craving for smoking and neural activity in response to smoking-related cues served as primary outcomes. Functional magnetic resonance imaging was performed during the memory reconsolidation process. The disruption of reconsolidation by propranolol decreased craving for smoking. Reactivity of the postcentral gyrus in response to smoking-related cues also decreased in the propranolol group after the reconsolidation manipulation. Functional connectivity between the hippocampus and striatum was higher during memory reconsolidation in the propranolol group. Furthermore, the increase in coupling between the hippocampus and striatum positively correlated with the decrease in craving after the reconsolidation manipulation in the propranolol group. Propranolol administration before memory reactivation disrupted the reconsolidation of smoking-related memories in smokers by mediating brain regions that are involved in memory and reward processing. These findings demonstrate the noradrenergic regulation of memory reconsolidation in humans and suggest that adjunct propranolol administration can facilitate the treatment of nicotine dependence. The present study was pre-registered at ClinicalTrials.gov (registration no. ChiCTR1900024412).

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On the structural connectivity of large-scale models of brain networks at cellular level

Scientific Reports ◽

10.1038/s41598-021-83759-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Giuseppe Giacopelli ◽

Domenico Tegolo ◽

Emiliano Spera ◽

Michele Migliore

Keyword(s):

Large Scale ◽

Brain Networks ◽

Structural Connectivity ◽

Network Models ◽

Brain Regions ◽

Cellular Level ◽

Scale Model ◽

Mathematical Framework ◽

Underlying Mechanisms ◽

Experimental Findings

AbstractThe brain’s structural connectivity plays a fundamental role in determining how neuron networks generate, process, and transfer information within and between brain regions. The underlying mechanisms are extremely difficult to study experimentally and, in many cases, large-scale model networks are of great help. However, the implementation of these models relies on experimental findings that are often sparse and limited. Their predicting power ultimately depends on how closely a model’s connectivity represents the real system. Here we argue that the data-driven probabilistic rules, widely used to build neuronal network models, may not be appropriate to represent the dynamics of the corresponding biological system. To solve this problem, we propose to use a new mathematical framework able to use sparse and limited experimental data to quantitatively reproduce the structural connectivity of biological brain networks at cellular level.

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Cannabinoids, reward processing, and psychosis

Psychopharmacology ◽

10.1007/s00213-021-05801-2 ◽

2021 ◽

Author(s):

Brandon Gunasekera ◽

Kelly Diederen ◽

Sagnik Bhattacharyya

Keyword(s):

Psychotic Disorders ◽

Neural Substrates ◽

Brain Regions ◽

Reward Processing ◽

Anterior Cingulate ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Future Research ◽

Drug Challenge ◽

Psychotomimetic Effects

Abstract Background Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. Aims We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. Methods This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis Results There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. Conclusions There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.

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