Overview Of Magnetic Resonance Imaging, Genomic And Neuroimaging Genomics Studies In ADHD
Introduction
Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent chronic, clinically heterogeneous neurodevelopmental disorder of inattention, impulsivity, and hyperactivity, affecting 5 to 7 % children, almost similar in adolescent and 2.5 to 4.9 % in adults worldwide. It has severe impact on development, schooling and overall quality of life and imposes significant economic burden on individual, family and society. Severity level and presentation of ADHD can change during a person’s lifetime, with adult patients displaying less obvious symptoms of hyperactivity and impulsivity. Approximately 55-75% still carry the diagnosis in adult-hood or emit only partially displaying several impairments also in adulthood.
ADHD, according to DSM-IV has been divided into three subtypes: a combined type (ADHD-C), which shares symptoms of hyperactivity and inattention, an inattentive type (ADHD- I), which exhibits primarily symptoms of inattention with no or few hyperactive/impulsive symptoms and a less common hyperactive type (ADHD-H), which shows hyperactive/impulsive symptoms but no or few difficulties in the domain of attention. Individuals with ADHD are more likely to experience comorbid psychiatric disorders. The majority of adults with ADHD have at least one lifetime psychiatric comorbidity including anxiety (47%), mood (38%), impulse control (20%), and substance use disorders (15%). The pathophysiology of ADHD is largely unknown, however, multiple factors are considered to be responsible for ADHD symptoms including genetic, neurodevelopmental, brain injury, environmental exposures, and consanguineous marriages.
Magnetic resonance imaging studies have reported global and local brain structural changes in gray matter volume, density, cortical thickness, and subcortical volumes, diminished white matter integrity on diffusion tensor imaging in ADHD children as compared to control using both region of interest and voxel-based morphometry. Functional imaging studies have clearly demonstrated that patients with ADHD have decreased functional activity on prefrontal and parietal cortex and increased in cingulate and sensory motor cortex suggesting both decreased and increased brain activities are responsible for severe form of ADHD. These brain changes has been correlated with clinical features of ADHD.
Recently, molecular genetic findings suggest strong genetic influence on ADHD with heritability rate ranging from 75 to 95 %. Multiple studies based on association, linkage and meta-analysis explored the genetic susceptibility of ADHD and observed number of susceptibility genes, variants, and chromosomal regions associated with ADHD. Genome-wide association studies (GWAS) discovered that genomic DNA copy number variants and rare or large deletion/duplications are also observed in ADHD. Studies using genome wide linkage and fine mapping found associations between ADHD and chromosome bands 16p13. Subsequently, fine mapping linkage analysis discovered variation in the gene encoding for LPHN3 (responsible for neuronal signaling) as a potential risk factor for ADHD. Recently, it is reported that multiple genes in ADHD showed association with various biological functions including neural development are abnormal in ADHD.Advancement in neuroimaging and molecular genetic technologies offers opportunity to examine the genetic effect on structural and functional brain changes in various neurological and psychiatric diseases. Recently, neuroimaging genomics has observed significant association of structural and functional brain changes with genetic variations in ADHD. Though, some preliminary studies have linked the neuroimaging and genomics to understand the pathophysiology of ADHD but the factors responsible for the ADHD are remain elusive.
Recently it is considered that intermediate phenotypes derived from neuroimaging can be used in order to understanding the disease pathologies more mechanistically caused by genomic changes to completely uncover the clinical phenotypes. Intermediate phenotypes are those features of a disease that are associated more closely to its neurobiology than clinical symptoms and contributes in genetic susceptibility with disease itself. Neuroimaging derived phenotypes, such as structural MRI and DTI parameters are having high heritability. These neuroimaging derived phenotypes are changes in ADHD and has been considered key intermediate phenotypes for the ADHD. Compared to existing reviews of brain imaging genetics studies in ADHD, this review is more focused by including childhood, adolescent and adult ADHD studies. Beyond the systematic review, we also emphasize the need for combinatorial approaches which can be achieved by combining imaging, cognitive and genomic components, which can provide insight from alternative angles into the biological pathways leading from an ADHD risk gene to disease.
Material and Methods
For this review, On XXX, we searched for all brain imaging modalities, and ADHD using PubMed and google scholar with the following search which include the individual key words or in combination Positron Emission Tomography in ADHD Brain imaging in ADHD, Brain magnetic resonance imaging in ADHD, Functional magnetic resonance imaging (fMRI), Structural magnetic resonance imaging in ADHD, Diffusion tensor imaging in ADHD, Magnetic Resonance Spectroscopy in ADHD, Genetics in ADHD, Genomic in ADHD, GWAS in ADHD, Imaging genetics in ADHD, Imaging genomics in ADHD.
Brain imaging changes in ADHD
ADHD may affects individual behavior likely govern through effects on brain system development and functioning. Multiple charectrstrcis such as development, maturation, structure, function, metabolites level, cerebral blood flow and connectivity have been found altered in the brain of ADHD. Besides MRI, two imaging techniques have showed brain changes in ADHD are positron emission tomography (PET) and single photon emission computed tomography. Both these techniques are based on the quantification of a radionuclide’s decay and have yielded enough sensitivity to measure the brain perfusion, metabolic activity, neurotransmitter fluctuation, and receptor systems and comparing between ADHD patients and controls. A meta-analysis based on 9 PET studies demonstrated higher (14%) striatal DAT density in ADHD patients as compared to healthy control.
Another study performed by Volkow and co-workers measured postsynaptic dopamine receptor availability and observed that medication-naive adults ADHD patients showed lower dopamine D2/D3 receptor availability in the left caudate compared to healthy controls. Further, same group demonstrated decreased dopamine activity in the caudate after administration of methylphenidate (MPH) in ADHD patients compared to controls. A study based on SPECT examined D2 receptor availability during MPH therapy in ADHD patients and observed that D2 receptor availability is considerably decreased in the striatum of these patients as compared to healthy controls.
Structural MRI changes in ADHD
Structural magnetic resonance imaging (sMRI) provides brain anatomical and pathological information non-invasively. It can be used effectively for measurement of brain volumetric changes, shape changes, tissue intensity changes, gray and white matter density changes ranging from cortical to subcortical area. SMRI scans are also used to overlay or map low resolution scans such as fMRI and DTI with associated structures.Gray matter density, and volume changes in ADHDIt has been reported that patients with ADHD showed lower total brain volume and gray matter volume (around 3-5%) as compared to controls. Multiple studies using ROI and voxel based analysis has been performed to explore the global and regional reduction in brain tissue. A meta-analysis observed significant volume reduction in cerebellar regions, total and right cerebral volume and subcortical regions including splenium and right caudate areas. Several meta-analysis studies using voxel-based morphometry (VBM) were performed to explore the gray matter intensity changes in these patients.
Meta-analysis studies by Ellison-Wright et al., 2008 et al, identified a significant regional gray matter reduction in ADHD in the right putamen/globus pallidus region and suggest that putamen/globus pallidus may be an anatomical marker for dysfunction in frontostriatal circuits mediating cognitive control. Another meta-analysis by Frodland Skokauskas et al., 2012 also observed similar finding with decreased caudate volumes on manual tracing was the additional brain sites as compared to Ellison-Wright et al., 2008. Another metanalysis performed by Nakao et al., 2011 et al., based on 14 studies observed that ADHD group had global reductions in gray matter volumes, which were robustly localized in the right lentiform nucleus and caudate nucleus. While another meta-analysis study with 931 patients with ADHD and 822 controls showed decreased gray matter volume in bilateral basal ganglia/insula as compared to controls.
A cross sectional study showed that Participants with ADHD had a 2.5% smaller total brain and 3% smaller total gray matter volume while total white matter volume was unaltered. However participants with ADHD had significantly smaller total caudate and total putamen volumes in the younger group. Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. A recent study based on 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls showed that ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para) cingulate cortices, however Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus).
Cortical, subcortical and gyrification changes in ADHD
Multiple studies has been performed in ADHD on developmental changes including cortical thickness, surface area, subcortical areas and gyrification. However developmental milestones underlying above changes are still not well clear. Recent development in post processing methodologies may improves and provide the new opportunity to explore more these changes with more precise which are considered have effect on neurodevelopmental outcomes. Reduction in cortical thickness has been reported by multiple studies, however few studies showed either increased or no changes. A study performed by Wolosin et al. 2009 showed reduced cortical thickens in these population.
Another study based on longitudinal data by Sara Ambrosino et al., subjects with ADHD had smaller overall cortical volume, predominantly driven by decreases in frontal lobe volume that were associated with reduced surface area and gyrification and nearly all decreases were stable across development. Other study showed simultaneous delay in the development of cortical thickness and surface area indicates that there may be a global perturbation of cortical maturation in ADHD. It has been reported that ADHD children showed altered cortical maturation. Normal brain development in early childhood is leads to increase in grey matter volume and over the course of development, neuronal populations are pruned to provide optimal functional efficiency, and alterations in gray matter or cortical thickness reflect the maturational of the brain. Shaw et al., observed delay of 2- to 3-year in cortical thickness development in both motor and sensory cortices of children with ADHD as compared to healthy children. Surface area, another component of brain maturation also showed developmental delay in ADHD, especially in right PFC.
A cross-sectional mega-analysis study on children and adults across 60 years of the lifespan by Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) ADHD Working Group observed significant smaller accumbens, amygdala, caudate, hippocampus, putamen, and ICV relative to controls. Effect sizes were highest in children, case-control differences were not present in adults. Explorative lifespan modeling suggested a delay of maturation and a delay of degeneration. Psychostimulant medication use or presence of comorbid psychiatric disorders did not influence results, nor did symptom scores correlate with brain volume.
Diffusion tensor imaging (DTI) changes in ADHD
Diffusion tensor imaging (DTI) is non-invasive MRI-based technique used to characterize white matter tissue microstructural integrity and microfiber pathways by exploiting diffusion properties of water molecules in the brain. Fractional anisotropy (FA) and mean diffusivity (MD) are most frequently used DTI-derived quantitative indices that have been used in various normal, pathological, and developmental brain studies. Higher FA values are thought to reflect greater directional coherence of diffusion in white matter and may indicate greater axonal integrity and organization, while MD values reflect an estimate of the magnitude of diffusion in white matter pathways. Other DTI derive metrix such as axial and radial diffusion metrix also provide additional microstructural information. Reductions in axial diffusion reflects perturbed axonal integrity and extra-axonal space, and reductions in radial diffusion suggest increased myelination and are sensitivity to crossing fibers. A met-analysis based on DTI finding between ADHD patients and healthy controls observed significant abnormal microstructural integrity in ADHD patients mainly located in white matter tracts subserving the frontostriatal-cerebellar neurocircuitry.
Most consistently, studies reported white matter anomalies in the corpus callosum in childhood ADHD and adult ADHD. However the precise pathological mechanism is not fully understood, decreased FA in CC of adults ADHD was driven by changes in RD rather than AD, indicating that abnormal myelination is a possible pathophysiological factor in adult ADHD. A recent study by Bouziane C et al., observed that ADHD children did not differ in FA values from control children, whereas adult ADHD subjects had reduced FA values when compared to adult controls in several regions. Zhao-Min Wu et al., performed a study on adolescent and observed that ADHD showed decreased FA and increased RD in widespread, overlapping brain regions, mainly in corpus callosum (CC) and major tracts in the left hemisphere and decreased FA was associated with inhibition performance in the participants with ADHD.
Another study based on adolescent and adults by van Ewijk H et al., 2014 using VBM observed that ADHD showed decreased FA and decreased MD in several widespread, non-overlapping brain regions. In contrast, higher ADHD symptom count was consistently associated with increased FA and decreased MD in the ADHD group. Unaffected siblings resembled individuals in the ADHD group with regard to decreased FA but had MD similar to that in healthy controls. A study performed by Onnink AM et al., relatively bigger sample size on adult population using TBSS ADHD showed reduced FA in corpus callosum, bilateral corona radiata, and thalamic radiation. Higher MD and RD were found in overlapping and even more widespread areas in both hemispheres, also encompassing internal and external capsule, sagittal stratum, fornix, and superior lateral fasciculus.
A meta-analysis by Chen L et al., using TBSS observed FA reductions in the splenium of the corpus callosum (CC) that extended to the right cingulum, right sagittal stratum, and left tapetum. The FA reduction in the CC splenium was negatively associated with the mean age of the ADHD group. More recent a metanalysis on children and adolescent by Aoki Y et al., WBVBA meta-analysis showed both significantly lower and higher FA values in individuals with ADHD; TBSS meta-analysis showed significantly lower FA in ADHD compared with TD in four clusters: two in the corpus callosum (isthmus and posterior midbody), one in right inferior fronto-occipital fasciculus, and one in left inferior longitudinal fasciculus. However, four of six datasets confirming no group-differences in motion showed no significant between-group FA differences.
