Compulsivity

Question 1

Compulsivity definition

Answer 1

Repetitive, irresistable urge to perform a behaviour, with loss of voluntary control over this intense urge and diminished ability to inhibit thoughts or actions leading to habitual acts

Question 2

Cross-disorder trait

Answer 2

Underlying phenotypically distinct psychiatric disorders that emerge throughout all stages of life

Early life (autism)
Late childhood (OCD)
Addiction (SUD)
ADHD associated with SUD

Question 3

Mechanisms underlying compulsivity

Answer 3

Cognitive
Neural
Genetic nature
Certain biomarkers underpinning association between compulsivity, impulsivity and addiction

Question 4

Primary brain mechanism investigated in relation to compulsivity

Answer 4

Corticostriatal glutamate circuit, where altered corticostriatal functional connectivity has been observed in OCD (Harrison et al. 2009)

Question 5

More recently observed

Answer 5

Abnormal corticostriatal limbic functional connectivity had been demonstrated in OCD patients during reward processing and during resting state, signifying the role of the nucleus accumbens in compulsive behaviour (Jung et al. 2013)

Question 6

Autism spectrum disorder (ASD)

Answer 6

Characterised by deficits in social interaction and communication, with stereotyped patterns of behaviour, interests and activities including repetitive motor behaviours and body movements.

Question 7

Comorbidity of ASD with ADHD

Answer 7

High comorbidity
25-50% of ASD individuals presenting with impulsivity, hyperactivity and attentional deficits qualifying for ADHD diagnosis

Question 8

ASD individuals demonstrate with….

Answer 8

3 fold increase in addictive behaviours and risk of SUD in adolescence

Question 9

Neurotransmitter hypothesis underlying compulsivity

Answer 9

Decreased serotonin levels, serving as basis for SSRI medication however 30-40% non response rate

Question 10

Dopaminergic overactivity in BG

Answer 10

Likely the cause of dysregulation in preventing certain actions or thoughts

Question 11

Dysregulation in frontal regions

Answer 11

Alterations in excitatory and inhibitory balance of glutamate and GABA

Question 12

Present hypothesis

Answer 12

In the trajectory of addictive behaviours, compulsivity originates prior to obsessions

Question 13

The TACTICS project (2012-2018)

Answer 13

Preclinical and clinical research to identify neural, genetic and molecular factors involved in pathogenesis of compulsivity

Question 14

Using a series of ‘proof-of-concept’ studies

Answer 14

cohesion of structural neuroimaging studies (MRI/DTI) neurochemistry (MRS/microdialysis) behaviour, genetics (GWAS) proteomics and Bayesian machine learning tools

Question 15

Male and female pediatric clinical populations and

Answer 15

behavioural animal mdels to better understand the mechanisms related to glutamate dysfunction in frontostriatal circuits and its remediation by early intervention studies with glutamate-based clinically used drugs

Question 16

Animal models of compulsive behaviour

Answer 16

provided valuable insights into mechanisms underpinning compulsivity as a cross-disorder trait

Question 17

Compulsive lever pressing in signal attenuation mouse model of OCD

Answer 17

differentiates between compulsive-like behaviours and behaviours that are repetitive but not compulsive

Question 18

Adminstration of quinpirole

Answer 18

selective D2 and D3 dopaminergic receptor agonist in rats led to compulsive checking behaviours implicating the role of basal ganglia hyperactivity in compulsivity

Question 19

SLITKR KO mice

Answer 19

impaired corticostriatal circuitry
compulsive behaviours in form of excessive barbering

Question 20

SSRI treatment (fluoxetine)

Answer 20

reduced overgrooming in SLITKR KO mice demonstrating the role of serotonin in compulsivity

Question 21

Reversal learning useful assessment

Answer 21

measure compulsivity in animal models with reduced behavioural flexibility indicative of compulsive-like behaviours

Question 22

Virtual reality environments

Answer 22

used to explore reversal learning in younf mice (Havenith et al. 2019)

Question 23

Error detection in reversal learning trial attributed to

Answer 23

ACC function with mice required to overcome learned avoidance of previously learned stimulus in order to acquire new association

Question 24

Impairments in reversal learning

Answer 24

observed in OCD patients (Remijinse, 2006)

Question 25

Phenotypic and MRI characterisation confirmed

Answer 25

dysregulated insulin signalling in TALLYHO/JngJ mouse model

Question 26

TALLYHO/JngJ demonstrate compulsive behaviour

Answer 26

with increased correction errors in touchscreen operant reversal learning and enhanced suppression of non-rewarded stimulus during appetitive extinction (Van de Vondervoort et al. 2018)

Question 27

GWAS identified

Answer 27

brain-localised insulin signalling as an important mechanism in OCD and compulsivity

Question 28

Top ranked SNPs from OCD genetic analyses

Answer 28

KCNQ1 potassium channel involved in insulin secretion
IGF1R target for compulsivity

Question 29

Proteomic analysis of TALLYHO/JngJ diabetic mice

Answer 29

Decreased KCNQ1 expression in cerebellum
Increased KCNQ1 and IGF1 gene expression in serum (Van de Vondervoort et al. 2018)

Question 30

MRI studies in TALLYHO/JngJ to examine structural and functional changes related to insulin signalling

Answer 30

identified alterations in white matter integrity

Question 31

relevance of white matter changes in TH mice

Answer 31

important based on role of insulin in regulation of lipid metabolism and stimulation of lipogenesis

Question 32

these ideas signify emerging role of….

Answer 32

insulin and IGF1 signalling in compulsive behaviour as opposed to the previous sole hypothesis of glutamate related mechanisms