In the present fMRI study, we investigated changes in regional cerebral activity and functional connectivity within brain networks underlying WM processes in children with ADHD. Importantly, our ADHD children population was carefully selected, naïve for any medication and devoid of the often-present co-morbidity, and behavioural performance was at the same level than in Controls, thus discarding the hypothesis that brain activity differences could be due to these confounding parameters. Possible limitations in the interpretation of our results are linked to the facts that having observing equal performance in the WM updating condition does not automatically imply that behavioural differences could not have been observed in more challenging conditions, and that cognitive resources needed to succeed to the task may already be differentially challenged in the two populations. Also, even if usually more robust, block-design fMRI approaches make that averaged cerebral activity over a block encompasses both the component of interest (i.e. the updating process in WM) and other less controlled cognitive processes differentiating performance on a target updating task (N-back 2) and on a control detection task (N0).
Notwithstanding, our results indicate at first glance similar patterns of working memory (WM)-related cerebral activity in ADHD and Control children, also in line with previous findings in healthy adults 
. Indeed, WM-related responses were found in a large cerebral network encompassing the bilateral premotor and dorsal cingulate/medial premotor cortex including the supplementary motor area (SMA), the bilateral dorsolateral and ventrolateral prefrontal cortex, the frontal pole, and bilaterally the medial posterior parietal cortex including the precuneus, the inferior parietal lobes, the medial/lateral cerebellum and the thalamus. Notwithstanding, between-group comparisons revealed decreased activation patterns in ADHD children in a widespread cortico-subcortical network encompassing the bilateral occipital and inferior parietal lobes, the caudate nucleus, the cerebellum and the functionally connected brainstem nuclei. As our study was performed in an homogeneous group of children with ADHD, in whom behavioural performance was unimpaired, these results yield evidence for different distributed networks in WM-related processes relevant to ADHD.
Decreased WM-related activity in the left occipital region is partially reminiscent of previous findings in ADHD adults 
, also in line with the report of a negative correlation between right inferior occipital activity and scores of inattention at the Conner’s scale, supporting an additional link between occipital activity and WM and/or visual attentional strategies 
. We additionally evidence here for the first time distinctive functional connectivity patterns in ADHD between occipital and cerebellar, striatal and neocortical regions involved in WM. Decreased activation has been observed during information maintenance in WM in the same occipital region, a phenomenon thought to participate in visual processing and top-down attentional modulation of posterior cortical activity 
. In this respect, specific deficits in top-down attentional control have been reported in children with ADHD, in association with a functional disconnection between frontal and occipital cortices 
. Hence WM-related deactivations in the occipital cortex may be linked to an organized mode of brain function, suspended as a necessary process to favour or optimize other brain resources necessary to perform on more complex components of the ongoing task 
Inferior parietal cortex (IPC) activity remained close to baseline under WM condition in ADHD children, whereas it markedly increased in Controls. A lack of WM-related activation in the IPC in ADHD corroborates findings from prior fMRI studies conducted in children, adolescent and adult populations with ADHD 
. At variance, we did not replicate findings of decreased superior parietal cortex activation in ADHD children 
and adolescents 
. Notwithstanding, our and past results consistently highlight a dysfunction in ADHD in parietal areas recognized to play an important role in attention and spatial processing. Following a meta-analysis of normative fMRI studies, the IPC but not the superior parietal lobe (SPL) is a major activation cluster in fMRI studies using various versions of the N-back WM paradigm 
, which may explain an absence of effect in the SPL.
WM-related changes in striatum activity have been previously reported in the ADHD 
. In the present study, whereas activity in the caudate nucleus, a region highly innervated by dopamine projections, increased in controls in the WM N2 condition, it decreased below baseline level in the ADHD population. The caudate nucleus is a crucial component in neural networks involved in executive and cognitive control of attention and WM, playing a pivotal role in the relay of connections between the frontal cortex and striatum 
. Furthermore, levels of caudate activation are related to specific processes underlying different aspects within WM, with information manipulation associated with higher signal intensity than retrieval 
. Dissociable striatal contributions to ADHD have also been highlighted 
, suggesting that executive function deficits are linked to anterior striatal activity 
. Interestingly, adolescents with ADHD both improved task performance and demonstrated decreased functional connectivity between middle frontal gyrus (MFG) and striatal regions compared to off medication on WM tasks 
. It suggests that there is an increased demand on the frontal circuitry in non-medicated ADHD subjects, supporting the hypothesis that basal ganglia function could lead to compensatory increase in activation in the prefrontal cortex in subjects with ADHD 
. Our own results demonstrating functional connectivity between caudate nucleus and MFG in ADHD children during WM are in agreement with this hypothesis. Additionally, morphometric MRI studies have found larger anatomical differences between ADHD and Controls in a set of regions including the right caudate, although between-study discrepancies make results globally inconsistent 
. Still, significant reductions in both right and left ventro-striatal volumes provide neuroanatomical evidence of alterations in the ventral striatum of ADHD children 
. Initially smaller caudate volume also normalizes in ADHD males during late adolescence, possibly reflecting the clinical evolution since some ADHD symptoms tend to decrease with age in certain patients 
. Also, striatal hypoperfusion with methylphenidate-related increase has been reported in ADHD in SPECT and PET imaging studies and functional neuroimaging studies have corroborated the important role played by the striatum in cognitive inhibitory deficits by showing reduced activations in frontal and striatum regions 
. Altogether, the striatum and its connectivity continue to represent a prime target for future imaging studies in ADHD.
Cerebellar activity at rest in adult ADHD participants was previously found increased in the vermis after methylphenidate administration normalizing behavioural symptoms, and associated with ADHD ratings in Crus II 
. Under WM conditions, decreased activity in right cerebellum Crus I in ADHD children was observed in ADHD children of the same age range than in the present study 
, as well as in the posterior cerebellum in ADHD adults 
. Differences in Crus I activity between ADHD and Control children provides additional evidence for genuine functional abnormalities of the cerebellum in ADHD. Taken together, there is now robust and growing evidence for a role of the cerebellum that expands beyond motor control, with replicable cerebellar responses in a variety of domains including language, attention, executive functions, spatial processing and verbal WM that affects cognitive processing 
. Additionally, specific neocerebellar regions are involved in distinct cognitive functions that participate in the executive control networks. Especially, lobules VI and VII (Crus I and Crus II, respectively) may selectively contribute to the parallel cortico-cerebellar loops involved in executive control and WM 
. A broad functional lateralization of the cerebellum has also been demonstrated, with a preferential involvement of the right and left cerebellum in verbal and spatial processes, respectively 
. Structural cerebellar abnormalities have been documented in ADHD involving among other subregions the lobule VII, as well as overall volume reductions in the right cerebellum 
. A longitudinal case-control study 
using volumetric regional measure further reported that whereas ADHD subjects exhibit a non-progressive volume decrease in the superior cerebellar vermis (including Crus I/lobule VIIA), those patients with worse clinical outcome additionally exhibit progressive volume reductions in the inferior posterior cerebellar lobes. It suggests that non-progressive deficit in the superior vermis in ADHD patients may represent a neuroanatomical basis for fundamental deficits in cognitive and affective processing that are resistant to plastic developmental changes in ADHD 
Additionally, our findings are the first to disclose tightened positive relationships under WM load in ADHD between cerebellar activity and BOLD signal changes in a brainstem area compatible with the red nucleus (RN). Available data suggest anatomical and functional relationships between the RN and a widespread sensorimotor, limbic and associative network that mainly plays a modulatory role in complex sensorimotor and cognitive processes such as WM 
. In this respect, the RN could relay information in the phonological loop passing through the cerebellum for phonological WM necessary for speech. Additionally, a brain resting state study reported that the RN displays strong functional coherence with associative prefrontal, insular, temporal, and parietal cortex, supporting a cognitive role, with clusters also observed in occipital cortex 
. The precise function played by the RN in ADHD symptoms remains to be elucidated.
Finally, our results failed to evidence any significant WM-related differences between ADHD and controls in prefrontal regions, although considered a critical neural substrate for WM in many studies 
. This lack of differences may be due to a more limited involvement of prefrontal regions in WM-related processes in childhood. Indeed, studies having investigated the neural patterns associated with WM in healthy children 
have reported roughly similar activation patterns during WM than in adults, but also highlighted different developmental networks in children, that may reflect different cognitive strategies and functional brain organization. While activation patterns in adult predominate in frontal and parietal regions, in children most pronounced activation patterns are found in the premotor and parietal cortex, anterior insula, caudate/putamen, and the cerebellum 
. A longitudinal study also provided evidence that, although most individuals recruit prefrontal cortex as expected during a WM task, this recruitment is correlated with behaviour only in late adolescence 
. Consequently, marked differences in prefrontal cortex activity during WM in children are not expected. Notwithstanding, we have evidenced functional connectivity patterns between striatal and prefrontal regions, suggesting a cooperative involvement in WM-related networks in ADHD. Alternatively, one may hypothesise that variations in frontal activity are mostly related to differences in behavioural performance, and consequently have been dampened in our experimental design, ADHD and Control children being equated on behavioural performance. Supporting this hypothesis, a supplementary analysis comparing ADHD children with a performance lower (n
8) or higher (n
11) than the median split UP score (reflecting the updating process in working memory) disclosed higher cerebral activity in middle frontal (standard coordinates −36 6 62 mm) but also middle occipital (34–78 28 mm) and inferior parietal (64 −26 30 mm) and precentral (46 −26 34 mm) regions (all p<.001 uncorrected). Future investigations are needed to assess the contribution of these parameters as well as anatomical and temporal functional connectivity, taking into account the heterogeneous development and maturation of brain networks in the ADHD. Nowadays, our results point towards the existence of specific neuroanatomical patterns of brain activity, within functionally related networks, which may constitute the neural underpinnings of the cognitive architecture of ADHD.