Table 2:

Brain Alterations Observed in Children with Chronic Pain

Default Mode Network	Brain Regions	medial frontal cortex, posterior cingulate or retrosplenial cortex, precuneus, inferior parietal cortex, lateral temporal cortex, and hippocampal formation
	Function	self-awareness processing self-referential mental activity and episodic memory monitoring internal thoughts, external goals, and future planning
	Alterations in IBS	mixed results regarding gray matter of the posterior cingulate cortex have been observed [Bhatt et al., 2019, Hubbard et al., 2016], and lower gray matter in the posterior cingulate has been associated greater abdominal pain [Hubbard et al., 2016]. mixed results regarding resting-state functional connectivity have been observed, with lower connectivity between the posterior cingulate and insula, but greater resting-state functional connectivity between the thalamus and posterior cingulate, and posterior cingulate and dorsolateral prefrontal cortex [Bhatt et al., 2019, Hubbard et al., 2016]
	Alterations in CRPS	lower gray matter in the lateral temporal cortex, dorsal posterior cingulate and precuneus [Erpelding et al., 2016] greater resting-state functional connectivity within the default-mode network. Following an intensive psycho-social treatment regimen, a decrease (shift towards normalization) in resting-state functional connectivity has been observed associated with decreased pain [Becerra et al., 2014]
	Alterations in Migraines	lower gray matter in the lateral temporal cortex, medial frontal cortex and precuneus [Faria et al., 2015, Rocca et al., 2014]
	Alterations in Sickle-Cell Disease	lower gray matter in the posterior cingulate and precuneus has been observed [Kirk et al., 2009] greater resting-state functional connectivity has been observed in the precuneus (associated with lower cognitive performance) and medial frontal cortex [Colombatti et al., 2016]
	Sex Difference	N/A
Sensorimotor Network	Brain Regions	thalamus, basal ganglia, sensorimotor cortex, posterior insula
	Function	central processing and modulation of visceral and somatic sensory information
	Alterations in IBS	lower gray matter in the basal ganglia and thalamus [Bhatt et al., 2019] greater resting-state functional connectivity between the caudate nucleus and precentral gyrus [Bhatt et al., 2019] decreased gray matter in the somatosensory cortex, putamen and posterior insula from 7–9 years of age [Gupta et al., 2015]
	Alterations in CRPS	lower gray matter in the primary motor cortex, supplementary motor area, caudate nucleus, putamen, nucleus accumbens, anterior thalamus, and greater gray matter in the posterior thalamus [Erpelding et al., 2016] Following an intensive psycho-social treatment regimen, increases from previously lower gray matter in the putamen, caudate nucleus, and thalamus was observed [Erpelding et al. 2016] greater resting-state functional connectivity within cortical areas of the sensorimotor network, but lower resting-state functional connectivity within the basal ganglia [Becerra et al., 2014]
	Alterations in Migraines	greater gray matter in the putamen which was negatively associated with disease duration. Girls with migraines exhibit greater gray matter in primary sensorimotor cortex, and primary motor cortex, but lower gray matter in the caudate nucleus and putaman compared to girl healthy controls. Boys with migraines exhibit greater gray matter in the primary motor cortex, but lower gray matter in the primary somatosensory cortex, supplementary motor area, thalamus, pallidum, putamen and caudate nucleus compared to boy healthy controls [Faria et al., 2015, Rocca et al., 2014]
	Alterations in Sickle-Cell Disease	lower gray matter in the thalamus, caudate nucleus, putamen, and pallidum [Kawadler et al., 2013]
	Sex Difference	During early puberty, boys with migraine exhibit greater gray matter in the primary somatosensory cortex, supplementary motor area, pallidum and caudate nucleus compared to girls. At mid-puberty, girls exhibit greater gray matter in primary somatosensory cortex, primary motor cortex, caudate nucleus, putamen, thalamus compared to boys [Faria et al., 2015]
Salience Network	Brain Regions	dorsal anterior cingulate cortex (dACC), anterior insula
	Function	response to subjective experience or expectation of any interoceptive and exteroceptive stimulus coordination of the appropriate attentional, behavioral, affective, and visceral responses to such stimuli
	Alterations in IBS	lower gray matter in the anterior cingulate cortex and dorsomedial prefrontal cortex [Bhatt et al., 2019, Gupta et al., 2015, Hubbard et al., 2016]
	Alterations in CRPS	lower gray matter in anterior mid-cingulate cortex [Erpelding et al., 2016] greater resting-state functional connectivity from the anterior insula to salience network and central executive network [Becerra et al,, 2014] following a psycho-social treatment regimen resting-state functional connectivity decreased in the orbitofrontal cortex, medial prefrontal cortex, and was associated with decreased pain [Becerra et al., 2014]
	Alterations in Migraine	lower gray matter in the orbitofrontal cortex [Rocca et al., 2014]
	Alterations in Sickle-Cell Disease	N/A
	Sex Difference	N/A
Emotion Regulation Network	Brain Regions	amygdala, hippocampus, hypothalamus, posterior anterior cingulate cortex, subgenual cingulate cortex
	Function	activated by perceived or real disruption in homeostasis generation of rapid feedback inhibition of amygdala, thereby limiting the magnitude and duration of network activity and related activity in the central autonomic network
	Alterations in IBS	N/A
	Alterations in CRPS	Lower gray matter in amygdala, anterior hippocampus. Higher gray matter in the posterior hippocampus [Erpelding et al., 2016] Following an intensive psycho-social treatment regimen, previously lower gray matter in the amygdala, hippocampus and parahippocampal gyrus increased in gray matter [Erpelding et al., 2016] Greater resting-state functional connectivity from the amygdala to the executive control, sensorimotor and salience networks. Lower resting-state functional connectivity from the amygdala to precuneus and occipital lobe [Simons et al., 2014] Following an intensive psycho-social treatment regimen, a decrease in resting-state functional connectivity between the amygdala various sensorimotor and salience parts of the brain have been observed [Simons et al., 2014]
	Alterations in Migraine	Lower gray matter in the subgenual anterior cingulate cortex compared to healthy controls [Rocca et al., 2014] Girls with migraines have greater gray matter in the hippocampus compared to healthy controls [Faria et al., 2015]
	Alterations in Sickle-Cell Disease	Lower gray matter in the hippocampus and amygdala [Kawadler et al., 2013]
	Sex Differences	Girls with migraines have greater resting-state functional connectivity between the amygdala and thalamus compared to boy’s with migraines and healthy controls [Faria et al., 2015] At early puberty, boys with migraine exhibit greater gray matter in the amygdala, compared to girls. At mid-puberty, girls exhibit greater gray matter in the amygdala compared to boys [Faria et al., 2015] Girls with migraine exhibit greater gray matter in amygdala compared to girl healthy controls. Boys with migraines exhibit lower gray matter in amygdala compared to boy healthy controls [Faria et al, 2015] boys with migraines exhibit lower resting-state functional connectivity from the amygdala to the thalamus and culmen [Faria et al., 2015]
Central Autonomic Network	Brain Regions	control centers in the pontine-medulla (including periaqueductal gray and hypothalamus), the central nucleus of the amygdala, and several cortical regions (including the anterior insula, anterior cingulate cortex, prefrontal and motor regions)
	Function	central control and modulation of the autonomic nervous system regulation of respiratory, cardiovascular, endocrine, and digestive activities during cognitive, affective, and motor tasks and sensations.
	Alterations in IBS	N/A
	Alterations in CRPS	Lower gray matter in the orbitofrontal cortex and anterior mid-cingulate cortex [Erpelding et al., 2016] Following an intensive psycho-social treatment regimen, previously lower gray matter in the hypothalamus increased [Erpelding et al. 2016]
	Alterations in Migraine	N/A
	Alterations in Sickle-Cell Disease	N/A
	Sex Differences	No reported sex differences in the central autonomic network to date
Central Executive Network	Brain Regions	lateral prefrontal cortices and posterior parietal cortex
	Function	activated during tasks involving executive functions such as attention, working memory, planning and response selection often co-activated with regions of the salience network, as the brain attempts to focus its limited processing capacity to only salient information via attention, working memory, planning and response selection
	Alterations in IBS	lower gray matter in the dorsolateral prefrontal cortex, posterior parietal cortex, middle frontal gyrus, and superior frontal gyrus [Bhatt et al., 2019, Hubbard et al., 2016] Lower resting-state functional connectivity between the anterior mid-cingulate cortex and posterior parietal cortex, greater resting-state functional connectivity between the thalamus and posterior parietal cortex [Bhatt et al., 2019]
	Alterations in CRPS	Lower gray matter in the dorsolateral prefrontal cortex and precuneus [Erpelding et al., 2016] Greater resting-state functional connectivity observed in the central executive network was decreased following an intensive psycho-social treatment regimen, associated with decreased pain [Becerra et al., 2014] Lower resting-state functional connectivity within the left fronto-parietal network [Becerra et al. 2014] Greater resting-state functional connectivity within the right fronto-parietal network [Becerra et al., 2014] Following an intensive psychosocial treatment regimen, previously lower gray matter in the dorsolateral prefrontal cortex increased [Erpelding et al., 2016] Reduced resting-state functional connectivity following an intensive psychosocial treatment regimen within the right fronto-parietal network was associated with decreased pain scores. Increased connectivity was associated with greater pain scores [Becerra et al., 2014]
	Alterations in Migraine	N/A
	Alterations in Sickle-Cell Disease	N/A
	Sex Differences	no reported sex differences in the central-executive network to date