Effects of comorbid disorders on reward processing and connectivity in adults with ADHD

AbstractADHD is a neurodevelopmental disorder with a long trajectory into adulthood where it is often comorbid with depression, substance use disorder (SUD) or obesity. Previous studies described a dysregulated dopaminergic system, reflected by abnormal reward processing, both in ADHD as well as in depression, SUD or obesity. No study so far however tested systematically whether pathologies in the brain’s reward system explain the frequent comorbidity in adult ADHD. To test this, we acquired MRI scans from 137 participants probing the reward system by a monetary incentive delay task (MIDT) as well as assessing resting-state connectivity with ventral striatum as a seed mask. No differences were found between comorbid disorders, but a significant linear effect pointed toward less left intrastriatal connectivity in patients depending on the number of comorbidities. This points towards a neurobiologically impaired reward- and decision-making ability in patients with more comorbid disorders. This suggests that less intrastriatal connectivity parallels disorder severity but not disorder specificity, while MIDT abnormalities seem mainly to be driven by ADHD.

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No effect of a dopaminergic modulation fMRI task by amisulpride and L-DOPA on reward anticipation in healthy volunteers

Psychopharmacology ◽

10.1007/s00213-020-05693-8 ◽

2020 ◽

Author(s):

Oliver Grimm ◽

Magdalena Nägele ◽

Lea Küpper-Tetzel ◽

Moritz de Greck ◽

Michael Plichta ◽

...

Keyword(s):

Healthy Volunteers ◽

Region Of Interest ◽

Reward System ◽

Blood Oxygen Level Dependent ◽

Brain Regions ◽

Reward Processing ◽

Activity Level ◽

Placebo Condition ◽

Reward Anticipation ◽

Monetary Incentive Delay

Abstract Rationale Dysregulation of dopaminergic neurotransmission, specifically altered reward processing assessed via the reward anticipation in the MID task, plays a central role in the etiopathogenesis of neuropsychiatric disorders. Objectives We hypothesized to find a difference in the activity level of the reward system (measured by the proxy reward anticipation) under drug administration versus placebo, in that amisulpride reduces, and L-DOPA enhances, its activity. Methods We studied the influence of dopamine agonist L-DOPA and the antagonist amisulpride on the reward system using functional magnetic resonance imaging (fMRI) during a monetary incentive delay (MID) task in n = 45 healthy volunteers in a randomized, blinded, cross-over study. Results The MID paradigm elicits strong activation in reward-dependent structures (such as ventral striatum, putamen, caudate, anterior insula) during reward anticipation. The placebo effect demonstrated the expected significant blood oxygen level–dependent activity in reward-dependent brain regions. Neither amisulpride nor L-DOPA led to significant changes in comparison with the placebo condition. This was true for whole-brain analysis as well as analysis of a pre-defined nucleus accumbens region-of-interest mask. Conclusion The present results cast doubt on the sensitivity of reward anticipation contrast in the MID task for assessing dopamine-specific changes in healthy volunteers by pharmaco-fMRI. While our task was not well-suited for detailed analysis of the outcome phase, we provide reasonable arguments that the lack of effect in the anticipation phase is not due to an inefficient task but points to unexpected behavior of the reward system during pharmacological challenge. Group differences of reward anticipation should therefore not be seen as simple representatives of dopaminergic states.

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Hyperactive/impulsive and inattention symptoms are associated with reduced ERP activity during different reward processing stages: Evidence from the electrophysiological Monetary Incentive Delay Task in adult ADHD

10.1101/817973 ◽

2019 ◽

Author(s):

M. P. Bennett ◽

H. Kiiski ◽

Z. Cao ◽

F. R. Farina ◽

R. Knight ◽

...

Keyword(s):

Visual Cues ◽

Adult Adhd ◽

Monetary Incentive ◽

Reward Processing ◽

Button Press ◽

Adhd Symptoms ◽

Symptom Dimensions ◽

Delay Task ◽

Monetary Incentive Delay Task ◽

Monetary Incentive Delay

AbstractHyperactivity/impulsivity and inattention are core symptoms dimensions in attention-deficit/hyperactivity disorder. Some approaches suggest that these symptoms arise from deficits in the ability to anticipate and process rewards. However, evidence is equivocal with regard to ADHD-related differences in brain activity during reward processing. The aim of this study was to investigate when, and how, reward-related ERP activity was associated with hyperactive/impulsive symptoms and inattention symptoms. Adults with ADHD (n=34) and matched comparison participants (n=36) completed an electrophysiological version of the Monetary Incentive Delay task. This task separates reward processing into two stages-namely, an anticipation stage and a delivery stage. During the anticipation stage, visual cues signalled a possible monetary incentive (i.e. a reward or loss). After a brief delay, the delivery stage began, and incentives were delivered contingent on a speeded button-press. Electroencephalogram activity was simultaneously sampled and incentive-related event relate potentials (ERPs) calculated. These data were then analysed by calculating multiple regression models, at each sample point, wherein the correlation between incentive-related ERPs and ADHD symptoms was estimated. Linear and curvilinear associations between ERP activity and ADHD symptoms were tested in each regression mode. Findings suggest that ADHD symptoms were associated ERP activity at different reward processing stages. Hyperactive/impulsive symptoms were associated with reduced ERP activity during the initial anticipation of rewards from 224-329 ms post-reward cue. Inattention symptoms were associated with reduced ERP activity during the initial delivery of rewards from 251-280 ms post-reward onset. Finally, extreme ends of hyperactive/impulsive and inattention symptoms were associated with reduced ERP activity towards the end of the anticipation stage from 500 ms post-reward cue onwards. These results support the idea that reward processing is disrupted in ADHD while also shedding new light on the dynamic relationship between ADHD symptom dimensions and the neurological mechanisms of reward processing.

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ADHD with Comorbid Bipolar Disorders: A Systematic Review of Neurobiological, Clinical and Pharmacological Aspects Across the Lifespan

Current Medicinal Chemistry ◽

10.2174/0929867326666190805153610 ◽

2019 ◽

Vol 26 (38) ◽

pp. 6942-6969 ◽

Cited By ~ 1

Author(s):

Federico Mucci ◽

Maria Teresa Avella ◽

Donatella Marazziti

Keyword(s):

Clinical Features ◽

Adult Adhd ◽

Neurodevelopmental Disorder ◽

Bipolar Disorders ◽

Mood Stabilizers ◽

Disruptive Behaviour ◽

Single Individual ◽

Pharmacological Management ◽

Long Time ◽

The Individual

Background: Attention deficit hyperactivity (ADHD) disorder is a neurodevelopmental disorder characterized by inattention, hyperactivity, disruptive behaviour, and impulsivity. Despite considered typical of children for a long time, the persistence of ADHD symptoms in adulthood gained increasing interest during the last decades. Indeed, its diagnosis, albeit controversial, is rarely carried out even because ADHD is often comorbid with several other psychiatric diosrders, in particular with bipolar disorders (BDs), a condition that complicates the clinical picture, assessment and treatment. Aims: The aim of this paper was to systematically review the scientific literature on the neurobiological, clinical features and current pharmacological management of ADHD comorbid with BDs across the entire lifespan, with a major focus on the adulthood. Discussion: The pharmacology of ADHD-BD in adults is still empirical and influenced by the individual experience of the clinicians. Stimulants are endowed of a prompt efficacy and safety, whilst non-stimulants are useful when a substance abuse history is detected, although they require some weeks in order to be fully effective. In any case, an in-depth diagnostic and clinical evaluation of the single individual is mandatory. Conclusions: The comorbidity of ADHD with BD is still a controversial matter, as it is the notion of adult ADHD as a distinct nosological category. Indeed, some findings highlighted the presence of common neurobiological mechanisms and overlapping clinical features, although disagreement does exist. In any case, while expecting to disentangle this crucial question, a correct management of this comorbidity is essential, which requires the co-administration of mood stabilizers. Further controlled clinical studies in large samples of adult ADHD-BD patients appear extremely urgent in order to better define possible therapeutic guidelines, as well as alternative approaches for this potentially invalidating condition.

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Reward Processing in Late Life Depression: Insights From the Monetary Incentive Delay Task

Biological Psychiatry ◽

10.1016/j.biopsych.2021.02.757 ◽

2021 ◽

Vol 89 (9) ◽

pp. S303-S304

Author(s):

Jack Kaufman ◽

Joseph Kim ◽

Anna Bradford ◽

Jacob Germain ◽

Victor Patron ◽

...

Keyword(s):

Late Life ◽

Monetary Incentive ◽

Reward Processing ◽

Late Life Depression ◽

Delay Task ◽

Monetary Incentive Delay Task ◽

Monetary Incentive Delay

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Modulation of anterior cingulate cortex reward and penalty signalling in medication-naive young-adult subjects with depressive symptoms following acute dose lurasidone

Psychological Medicine ◽

10.1017/s0033291718003306 ◽

2019 ◽

Vol 49 (08) ◽

pp. 1365-1377 ◽

Cited By ~ 4

Author(s):

Selina A. Wolke ◽

Mitul A. Mehta ◽

Owen O'Daly ◽

Fernando Zelaya ◽

Nada Zahreddine ◽

...

Keyword(s):

Depressive Symptoms ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Reward Processing ◽

Anterior Cingulate ◽

Depression Severity ◽

Placebo Condition ◽

Double Blind ◽

Monetary Incentive Delay ◽

Reward Functions

AbstractBackgroundAberrations in reward and penalty processing are implicated in depression and putatively reflect altered dopamine signalling. This study exploits the advantages of a placebo-controlled design to examine how a novel D2antagonist with adjunctive antidepressant properties modifies activity in the brain's reward network in depression.MethodsWe recruited 43 medication-naïve subjects across the range of depression severity (Beck's Depression Inventory-II score range: 0–43), including healthy volunteers, as well as people meeting full-criteria for major depressive disorder. In a double-blind placebo-controlled cross-over design, all subjects received either placebo or lurasidone (20 mg) across two visits separated by 1 week. Functional magnetic resonance imaging with the Monetary Incentive Delay (MID) task assessed reward functions via neural responses during anticipation and receipt of gains and losses. Arterial spin labelling measured cerebral blood flow (CBF) at rest.ResultsLurasidone altered fronto-striatal activity during anticipation and outcome phases of the MID task. A significant three-way Medication-by-Depression severity-by-Outcome interaction emerged in the anterior cingulate cortex (ACC) after correction for multiple comparisons. Follow-up analyses revealed significantly higher ACC activation to losses in high-v.low depression participants in the placebo condition, with a normalisation by lurasidone. This effect could not be accounted for by shifts in resting CBF.ConclusionsLurasidone acutely normalises reward processing signals in individuals with depressive symptoms. Lurasidone's antidepressant effects may arise from reducing responses to penalty outcomes in individuals with depressive symptoms.

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Aberrant reward dynamics in trait anticipatory anhedonia

Social Cognitive and Affective Neuroscience ◽

10.1093/scan/nsz062 ◽

2019 ◽

Vol 14 (8) ◽

pp. 899-909

Author(s):

Shiyu Zhou ◽

Lu Nie ◽

Zhao Wang ◽

Mengyao Wang ◽

Ya Zheng

Keyword(s):

Clinical Sample ◽

Reward Processing ◽

Event Related Potential ◽

Behavioral Performance ◽

Current Event ◽

Disease States ◽

Monetary Incentive Delay ◽

Anticipatory Anhedonia ◽

Cardinal Feature

Abstract As a cardinal feature of several psychiatric disorders, anhedonia includes a consummatory component (deficits in hedonic response to rewards) and an anticipatory component (a reduced motivation to pursue them). Although being conceptualized as impairments of reward system, the neural characterization of reward processing in anhedonia is hampered by the enormous heterogeneity in the reward phase (‘wanting’ vs ‘liking’) and comorbidity (inherent to disease states). The current event-related potential (ERP) study examined the reward dynamics of anticipatory anhedonia in a non-clinical sample. Anticipatory and consummatory ERP components were assessed with a monetary incentive delay task in a high anticipatory anhedonia (HAA) group and a low anticipatory anhedonia (LAA) group. HAA vs LAA group showed a diminished reward-related speeding during behavioral performance and reported overall reduced positive affect during anticipation and receipt of outcomes. Importantly, neural dynamics underlying reward processing were negatively associated with anticipatory anhedonia across the anticipatory phase indexed by the contingent negative variation and the consummatory phase indexed by the feedback P3. Our results suggest that anticipatory anhedonia in non-clinical individuals is linked to a poor modulation during both anticipatory and consummatory phases of reward processing.

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Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations

Neurology Genetics ◽

10.1212/nxg.0000000000000387 ◽

2020 ◽

Vol 6 (1) ◽

pp. e387 ◽

Cited By ~ 7

Author(s):

Annalisa Vetro ◽

Tiziana Pisano ◽

Silvia Chiaro ◽

Elena Procopio ◽

Azzurra Guerra ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Brain Mri ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Premature Death ◽

Epileptic Encephalopathy ◽

Whole Exome ◽

Mri Scans ◽

Severe Hypotonia ◽

Profound Disability

ObjectiveTo describe clinical, biochemical, and molecular genetic findings in a large inbred family in which 4 children with a severe early-onset epileptic-dyskinetic encephalopathy, with suppression burst EEG, harbored homozygous mutations of phosphatidylinositol glycan anchor biosynthesis, class P (PIGP), a member of the large glycosylphosphatidylinositol (GPI) anchor biosynthesis gene family.MethodsWe studied clinical features, EEG, brain MRI scans, whole-exome sequencing (WES), and measured the expression of a subset of GPI-anchored proteins (GPI-APs) in circulating granulocytes using flow cytometry.ResultsThe 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia, associated with infantile spasms, focal, tonic, and tonic-clonic seizures and a burst suppression EEG pattern. Two of the children died prematurely between age 2 and 12 years; the remaining 2 children are aged 2 years 7 months and 7 years 4 months. The homozygous c.384del variant of PIGP, present in the 4 patients, introduces a frame shift 6 codons before the expected stop signal and is predicted to result in the synthesis of a protein longer than the wild type, with impaired functionality. We demonstrated a reduced expression of the GPI-AP CD16 in the granulocytic membrane in affected individuals.ConclusionsPIGP mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy with profound disability and premature death. CD16 is a valuable marker to support a genetic diagnosis of inherited GPI deficiencies.

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Effects of 12-Week Methylphenidate Treatment on Neurometabolism in Adult Patients with ADHD: The First Double-Blind Placebo-Controlled MR Spectroscopy Study

Journal of Clinical Medicine ◽

10.3390/jcm9082601 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2601

Author(s):

Simon Maier ◽

Ludger Tebartz van Elst ◽

Alexandra Philipsen ◽

Thomas Lange ◽

Bernd Feige ◽

...

Keyword(s):

Adult Adhd ◽

Neurodevelopmental Disorder ◽

Synaptic Cleft ◽

Anterior Cingulate ◽

Cerebellar Hemisphere ◽

Control Group ◽

Resonance Spectroscopy ◽

Double Blind ◽

Neuronal Tissue ◽

Metabolite Concentrations

Attention deficit hyperactivity disorder (ADHD) is a frequent neurodevelopmental disorder that often persists into adulthood. Methylphenidate (MPH) is the first-line treatment for ADHD; however, despite its wide usage, little is known about its neurometabolic effects. Until now, no randomized and blinded clinical trials have been conducted addressing the neurometabolic signals of MPH administration in adults with ADHD. In the current study, the authors investigated how MPH intake and group psychotherapy (GPT) influence brain neurometabolism over the course of three months. The authors hypothesized a decrease in the anterior cingulate cortex (ACC) glutamate concentration following MPH administration. This study was part of a double-blind multicenter trial (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS)) investigating the effects of MPH and GPT in patients with adult ADHD. Using single-voxel magnetic resonance spectroscopy (MRS) of the pregenual ACC and the left cerebellar hemisphere (CHL), we investigated the concentration of glutamate plus glutamine (Glx), N-acetyl-aspartate, creatine, total choline containing compounds, and myo-inositol in patients before and after 12 weeks of treatment. Neither MPH nor GPT significantly influenced the Glx concentration or any of the other metabolite concentrations in the ACC and CHL after 12 weeks. Therefore, contrary to the hypothesis, no change in the prefrontal Glx signal was detected after MPH treatment. Given that MRS does not differentiate between glutamate in the synaptic cleft and in neuronal tissue, MPH-induced down-regulation of glutamatergic neurotransmission in the ACC might only affect the concentration of glutamate in the synaptic cleft, while the general availability of glutamate in the respective neuronal tissue might be unaffected by MPH intake. The observed lack of any MPH-induced normalization in metabolite concentrations is less surprising, considering that the baseline sample did not significantly differ from a healthy control group. Future studies of other regions, such as the basal ganglia, and the use of novel methods, such as whole brain MRS and multimodal imaging approaches, are necessary.

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The relation between dopamine D2 receptor blockade and the brain reward system: a longitudinal study of first-episode schizophrenia patients

Psychological Medicine ◽

10.1017/s0033291718004099 ◽

2019 ◽

Vol 50 (2) ◽

pp. 220-228 ◽

Cited By ~ 6

Author(s):

Sanne Wulff ◽

Mette Ødegaard Nielsen ◽

Egill Rostrup ◽

Claus Svarer ◽

Lars Thorbjørn Jensen ◽

...

Keyword(s):

Longitudinal Study ◽

Reward System ◽

Reward Processing ◽

Psychotic Symptoms ◽

First Episode ◽

Receptor Blockade ◽

Fmri Signal ◽

Brain Reward ◽

First Episode Schizophrenia ◽

The Brain

AbstractBackgroundPsychotic symptoms have been linked to salience abnormalities in the brain reward system, perhaps caused by a dysfunction of the dopamine neurotransmission in striatal regions. Blocking dopamine D2 receptors dampens psychotic symptoms and normalises reward disturbances, but a direct relationship between D2 receptor blockade, normalisation of reward processing and symptom improvement has not yet been demonstrated. The current study examined the association between blockade of D2 receptors in the caudate nucleus, alterations in reward processing and the psychopathology in a longitudinal study of antipsychotic-naïve first-episode schizophrenia patients.MethodsTwenty-two antipsychotic-naïve first-episode schizophrenia patients (10 males, mean age 23.3) and 23 healthy controls (12 males, mean age 23.5) were examined with single-photon emission computed tomography using 123I-labelled iodobenzamide. Reward disturbances were measured with functional magnetic resonance imaging (fMRI) using a modified version of the monetary-incentive-delay task. Patients were assessed before and after 6 weeks of treatment with amisulpride.ResultsIn line with previous results, patients had a lower fMRI response at baseline (0.2 ± 0.5 v. 0.7 ± 0.6; p = 0.008), but not at follow-up (0.5 ± 0.6 v. 0.6 ± 0.7), and a change in the fMRI signal correlated with improvement in Positive and Negative Syndrome Scale positive symptoms (ρ = −0.435, p = 0.049). In patients responding to treatment, a correlation between improvement in the fMRI signal and receptor occupancy was found (ρ = 0.588; p = 0.035).ConclusionThe results indicate that salience abnormalities play a role in the reward system in schizophrenia. In patients responding to a treatment-induced blockade of dopamine D2 receptors, the psychotic symptoms may be ameliorated by normalising salience abnormalities in the reward system.

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