Jilly Naaijen

Fronto-striatal glutamatergic compounds in compulsive and impulsive syndromes: A review of magnetic resonance spectroscopy studies

Compulsivity and impulsivity are cross-disorder traits observed in autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Aberrant fronto-striatal glutamatergic signalling is core to the understanding of compulsive and impulsive disorders. In this review, the glutamate (Glu) neurochemistry of fronto-striatal circuits in paediatric and adult ASD, ADHD and OCD, as described in 59 studies, is outlined from the perspective of proton magnetic resonance spectroscopy ((1)H MRS). Despite the methodological inconsistencies between studies, two observations stand out that form possible hypotheses for future studies. Firstly, a possible increase in Glx (combination of Glu, glutamine and GABA) in the striatum across ADHD, OCD and ASD. Secondly, an increased Glx signal in the anterior cingulate cortex in paediatric ASD and ADHD but a lower Glx signal in adult ASD and ADHD. This suggests neurodevelopmental changes in fronto-striatal glutamatergic circuits across the lifespan. Future studies should incorporate more homogeneous samples, perform MRS at field strengths of at least 3 Tesla and provide much more precise and standardized information on methods to improve our understanding of fronto-striatal glutamatergic transmission in compulsive and impulsive syndromes.

Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: Association to overlapping traits in ADHD and autism

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.

Gut microbiome in ADHD and its relation to neural reward anticipation

Background Microorganisms in the human intestine (i.e. the gut microbiome) have an increasingly recognized impact on human health, including brain functioning. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with abnormalities in dopamine neurotransmission and deficits in reward processing and its underlying neuro-circuitry including the ventral striatum. The microbiome might contribute to ADHD etiology via the gut-brain axis. In this pilot study, we investigated potential differences in the microbiome between ADHD cases and undiagnosed controls, as well as its relation to neural reward processing. Methods We used 16S rRNA marker gene sequencing (16S) to identify bacterial taxa and their predicted gene functions in 19 ADHD and 77 control participants. Using functional magnetic resonance imaging (fMRI), we interrogated the effect of observed microbiome differences in neural reward responses in a subset of 28 participants, independent of diagnosis. Results For the first time, we describe gut microbial makeup of adolescents and adults diagnosed with ADHD. We found that the relative abundance of several bacterial taxa differed between cases and controls, albeit marginally significant. A nominal increase in the Bifidobacterium genus was observed in ADHD cases. In a hypothesis-driven approach, we found that the observed increase was linked to significantly enhanced 16S-based predicted bacterial gene functionality encoding cyclohexadienyl dehydratase in cases relative to controls. This enzyme is involved in the synthesis of phenylalanine, a precursor of dopamine. Increased relative abundance of this functionality was significantly associated with decreased ventral striatal fMRI responses during reward anticipation, independent of ADHD diagnosis and age. Conclusions Our results show increases in gut microbiome predicted function of dopamine precursor synthesis between ADHD cases and controls. This increase in microbiome function relates to decreased neural responses to reward anticipation. Decreased neural reward anticipation constitutes one of the hallmarks of ADHD.

Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder

Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8–13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model. Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. In addition, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared with controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.

Basal Ganglia Structure in Tourette's Disorder and/or Attention-Deficit/Hyperactivity Disorder

Tourettes disorder and attention‐deficit/hyperactivity disorder often co‐occur and have both been associated with structural variation of the basal ganglia. However, findings are inconsistent and comorbidity is often neglected.

Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder

Objective Both Tourettes disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently investigated in prior studies. Method We used proton magnetic resonance spectroscopy (1H-MRS) in children between 8 and 12 years of age (TD n = 15, ADHD n = 39, TD + ADHD n = 29, and healthy controls n = 53) as an in vivo method of evaluating glutamate concentrations in the fronto-striatal circuit. Spectra were collected on a 3 Tesla Siemens scanner from two voxels in each participant: the anterior cingulate cortex (ACC) and the left dorsal striatum. LC-model was used to process spectra and generate glutamate concentrations in institutional units. A one-way analysis of variance was performed to determine significant effects of diagnostic group on glutamate concentrations. Results We did not find any group differences in glutamate concentrations in either the ACC (F(3132) = 0.97, p = 0.41) or striatum (F(3121) = 0.59, p = 0.62). Furthermore, variation in glutamate concentration in these regions was unrelated to age, sex, medication use, IQ, tic, or ADHD severity. Obsessive–compulsive (OC) symptoms were positively correlated with ACC glutamate concentration within the participants with TD (rho = 0.35, puncorrected = 0.02). Conclusion We found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.OBJECTIVE Both Tourettes disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently investigated in prior studies. METHOD We used proton magnetic resonance spectroscopy (1H-MRS) in children between 8 and 12years of age (TD n=15, ADHD n=39, TD+ADHD n=29, and healthy controls n=53) as an in vivo method of evaluating glutamate concentrations in the fronto-striatal circuit. Spectra were collected on a 3Tesla Siemens scanner from two voxels in each participant: the anterior cingulate cortex (ACC) and the left dorsal striatum. LC-model was used to process spectra and generate glutamate concentrations in institutional units. A one-way analysis of variance was performed to determine significant effects of diagnostic group on glutamate concentrations. RESULTS We did not find any group differences in glutamate concentrations in either the ACC (F(3132)=0.97, p=0.41) or striatum (F(3121)=0.59, p=0.62). Furthermore, variation in glutamate concentration in these regions was unrelated to age, sex, medication use, IQ, tic, or ADHD severity. Obsessive-compulsive (OC) symptoms were positively correlated with ACC glutamate concentration within the participants with TD (rho=0.35, puncorrected=0.02). CONCLUSION We found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.

Handling hybrid and missing data in constraint-based causal discovery to study the etiology of ADHD

Causal discovery is an increasingly important method for data analysis in the field of medical research. In this paper, we consider two challenges in causal discovery that occur very often when working with medical data: a mixture of discrete and continuous variables and a substantial amount of missing values. To the best of our knowledge, there are no methods that can handle both challenges at the same time. In this paper, we develop a new method that can handle these challenges based on the assumption that data are missing at random and that continuous variables obey a non-paranormal distribution. We demonstrate the validity of our approach for causal discovery on simulated data as well as on two real-world data sets from a monetary incentive delay task and a reversal learning task. Our results help in the understanding of the etiology of attention-deficit/hyperactivity disorder (ADHD).

COMPULS: design of a multicenter phenotypic, cognitive, genetic, and magnetic resonance imaging study in children with compulsive syndromes

BackgroundCompulsivity, the closely linked trait impulsivity and addictive behaviour are associated with several neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive compulsive disorder (OCD). All three disorders show impaired fronto-striatal functioning, which may be related to altered glutamatergic signalling. Genetic factors are also thought to play an important role in the aetiology of compulsivity-related disorders.MethodsThe COMPULS study is a multi-center study designed to investigate the relationship between the traits compulsivity, impulsivity, and, to a lesser extent, addictive behaviour within and across the neurodevelopmental disorders ADHD, ASD, and OCD. This will be done at the phenotypic, cognitive, neural, and genetic level. In total, 240 participants will take part in COMPULS across four different sites in Europe. Data collection will include diagnostic interviews, behavioural questionnaires, cognitive measures, structural, functional and spectral neuroimaging, and genome-wide genetic information.DiscussionThe COMPULS study will offer the unique opportunity to investigate several key aspects of compulsivity across a large cohort of ADHD, ASD and OCD patients.

Anterior cingulate cortex glutamate and its association with striatal functioning during cognitive control

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by structural, functional and neurochemical alterations of the fronto-striatal circuits and by deficits in cognitive control. In particular, ADHD has been associated with impairments in top-down fronto-striatal glutamate-signalling. However, it is unknown whether fronto-striatal glutamate is related to cognitive control dysfunction. Here we explored whether and how anterior cingulate cortex (ACC) glutamate relates to striatal BOLD-responses during cognitive control. We used proton magnetic resonance spectroscopy to evaluate glutamate-to-creatine ratios in 62 participants (probands with ADHD n=19, unaffected siblings n=24 and typical controls n=19, mean age=20.4). Spectra were collected from the ACC and the dorsal striatum and glutamate-to-creatine ratios were extracted. Thirty-two participants additionally took part in a functional magnetic resonance imaging (fMRI) Stroop task to investigate neural responses during cognitive control. Given small sample sizes we report all effects with p<0.10 along with effect sizes. ADHD subjects showed decreased glutamate-to-creatine ratios in the ACC (F=3.81, p=0.059, ηp2=0.104; medium to large effect-size) compared with controls. Importantly, decreased ACC glutamate-to-creatine ratios were associated with increased striatal BOLD-responses during cognitive control (rho=-0.41, p=0.019; medium effect-size), independent of diagnosis. Increased striatal responses tended to be associated with more errors during the task and more hyperactivity/impulsivity symptoms (rho=0.34, p=0.058 and rho=0.33, p=0.068, respectively); the latter two being correlated too (rho=0.37, p=0.037), all with medium effect sizes. Our results suggest that ACC glutamate in ADHD might be associated with striatal (dys)functioning during the Stroop task, supporting the role of fronto-striatal glutamate in cognitive control.

Multi-modal imaging investigation of anterior cingulate cortex cytoarchitecture in neurodevelopment

Multi-modal imaging may improve our understanding of the relationship between cortical morphology and cytoarchitecture. To this end we integrated the analyses of several magnetic resonance imaging (MRI) and spectroscopy (MRS) metrics within the anterior cingulate cortex (ACC). Considering the ACCs role in neurodevelopmental disorders, we also investigated the association between neuropsychiatric symptoms and the various metrics. T1 and diffusion-weighted MRI and 1H-MRS (ACC voxel) data along with phenotypic information were acquired from children (8-12 years) with various neurodevelopmental disorders (n=95) and healthy controls (n=50). From within the MRS voxel mean diffusivity (MD) of the grey matter fraction, intrinsic curvature (IC) of the surface and concentrations of creatine, choline, glutamate, N-acetylaspartate and myo-inositol were extracted. Linear models were used to investigate if the neurochemicals predicted MD and IC or if MD predicted IC. Finally, measures of various symptom severities were included to determine the influence of symptoms of neurodevelopmental disorders. All five neurochemicals inversely predicted MD (all puncorrected<0.04, β=0.23-0.36). There was no association between IC and MD or IC and the neurochemicals (all p>0.05). Severity of autism symptoms related positively to MD (puncorrected=0.002, β=0.39). Our findings support the notion that the neurochemicals relate to cytoarchitecture within the cortex. Additionally, we showed that autism symptoms across participants relate to the ACC cytoarchitecture.