People with ADHD affected brain regions

• 1. People with ADHD affected brain regions
• 2. Volume changes in brain regions with ADHD
• 3. White substance
• 4. Gray matter
• 5. Myelination
• 6. Cerebral blood flow (CBF)

1. People with ADHD affected brain regions¶

ADHD is associated with changes in various regions of the brain:

• PFC
  • DlPFC
  • MPFC
  • OlPFC
• Basal ganglia¹
  • Striatum
    • Nucleus caudates
• Thalamus²
• Cerebellum¹
• Corpus callosum¹
• Significant hypoactivation in³
  • Several frontal-temporal brain regions
  • Right postcentral gyrus
  • Left insula
  • Corpus callosum
• Fusiform gyrus in the temporal lobe²

fMRI studies during task performance found reduced activation of fronto-striatal and fronto-parietal brain networks involved in cognitive control, timing and reward processing⁴

An analysis of car crashes in unaffected individuals found a correlation between percuneus volume and car crashes consistent with changes in ADHD.⁵

One study found no structural change in the substantia nigra in adults with ADHD.⁶

2. Volume changes in brain regions with ADHD¶

In ADHD, the volume of various brain regions is altered, and usually reduced.
It is possible that signaling pathways mediating apoptosis, autophagy and oxidative stress could play a role in the variability of volumetric differences between people with and without ADHD.⁷

In children with ADHD, studies found that compared to non-affected children

• Total brain volume reduced
  • (by 4 %)⁸
• Caudates reduced (meta-analysis of k = 23 studies with n = 3,200 children and adults aged 4 - 63 years)⁹⁸¹⁰
• Cortex (compared to non-affected persons)¹¹
  • ADHD medication attenuated the volume reduction in the cortex (minus 3.2 % instead of minus 5.8 %)¹²
  • ASS:
    • Greater cortical thickness
    • Larger cortex volume in the upper temporal cortex
    • Gender-specific
    • No interaction Age / diagnosis
  • ADHD:
    • More global increase in cortical thickness
    • Had a smaller cortical volume and a smaller surface area in a large part of the cortex
    • Independent of gender
    • Age / diagnosis interaction
    • Higher ADHD PRS correlated with reduced cortical thickness in bilateral transverse temporal regions in adults¹³
  • AuDHS: unique pattern of
    * Widespread increase in cortical thickness
    * Certain decrease of the surface
• PFC¹⁴
  • Anterior PFC reduced⁸
  • Orbital PFC reduced, predominantly on the right¹⁵
  • Right middle temporal gyrus in children with ADHD¹⁶
• Inferior dorsolateral frontal region¹⁵
• Basal ganglia
  • Right¹⁴
  • Striatum
    • Downsized¹⁵
    • Enlarged¹⁷
  • Pallidum (globus pallidus)
    • Reduced^{8 15}
    • Unchanged (meta-analysis of k = 23 studies with n = 3,200 children and adults aged 4 - 63 years)⁷
  • Nucleus accumbens
    • Reduced (meta-analysis of k = 23 studies with n = 3,200 children and adults aged 4 - 63 years)⁹
  • Putamen
    • Reduced (meta-analysis of k = 23 studies with n = 3,200 children and adults aged 4 - 63 years)⁹
    • Changed¹⁰
• Cerebellum
  • Reduced ¹⁰¹⁴
    • ADHD medication attenuated the volume reduction in the cerebellum (minus 3.5 % instead of minus 6.2 %)¹²
  • Enlarged¹⁷
• Vermis (Central vermis area)
  • Predominantly reduced on the right⁸¹⁵
• ACC
  • Reduced, mostly underactivated¹⁵
• Corpus callosum¹⁴
  • Splenium (beam bulge) reduced¹⁵¹⁸
• Thalamus
  • Changed¹⁰
  • Hypoactive¹⁹
  • Unchanged (meta-analysis of k = 23 studies with n = 3,200 children and adults aged 4 - 63 years)⁹
• Amygdala
  • Reduced (meta-analysis of k = 23 studies with n = 3,200 children and adults aged 4 - 63 years)⁹, bilateral²⁰
  • Smaller bilateral amygdala volume correlated with inattention and hyperactivity/impulsivity²⁰
• Hippocampus
  • Reduced (meta-analysis of k = 23 studies with n = 3,200 children and adults aged 4 - 63 years)⁹

The effects are stronger in boys than in girls, which correlates with the Polygenic Risk Score.¹⁰

One study investigated structural and functional changes in the glymphatic system in treatment-free children with ADHD. The cerebral volume of the Virchow-Robin spaces was increased by 32 % (15.514 mL vs. 11.702 mL).²¹

Interestingly, the reductions in the size of certain brain regions that are usually observed from the age of 60 appear to be less pronounced in ADHD. This is discussed as a neuroprotective factor of ADHD. It remains to be seen whether this is a consequence of ADHD itself or of stimulant treatment.
This is particularly significant in brain regions in which a strong loss of volume correlates with cognitive impairment and Alzheimer’s, such as the hippocampus and amygdala.²²

3. White substance¶

The white matter consists mainly of neurons and their extensions (axons). Myelinated axons look white.

A meta-analysis of 129 studies with n = 6739 people with ADHD and n = 6476 controls found conspicuous changes in the posterior interhemispheric connections responsible for the cognitive and motor functions affected by ADHD:²³

• reduced fractional anisotropy (FA) in the projection, commissural and association pathways, which correlated with symptom severity and cognitive deficits
• consistently reduced FA in the splenium and corpus callosum, extending to the cingulum
• lower FA was only found in old age, not in children
  • possibly due to the late development of callosal fibers

ADHD was found to have significantly increased axial diffusivity in the right cingulum bundle.²⁴

White matter was significantly reduced in children with ADHD. ADHD medication attenuated the reduction in white matter volume (minus 8.9 % instead of minus 10.7 %).¹²

Children with ADHD showed microstructural changes and alterations in long-range white matter connections. Learning problems and hyperactivity/impulsivity correlated negatively with the mean FA value in the right forceps major (the occipital part of the fibers of the corpus callosum), the left IFOF and the left genu capsulae internae.²⁵

Gray matter-white matter-tissue contrast (GWC) was elevated in 8 to 15 year old boys with ADHD, within the²⁶

• lingual regions bilaterally
• insular regions bilaterally
• transverse temporal regions on the left
  • this increase correlated with reduced inattention
• parahippocampal regions on the right
• pericalcarine regions right

The cortical thickness was unchanged.²⁶

DTI findings showed abnormalities in white matter integrity, particularly in:²⁷

• fronto-striatal circuits
• cerebellar circuits
• in the connections between corpus callosum and cingulum

4. Gray matter¶

MRI studies found a reduced volume of gray matter in regions important for executive functions in ADHD:⁴

• PFC
• Basal ganglia
• Cerebellum

as well as indications of delayed cortical maturation.

• Largest reductions in gray matter in:²⁸
  • Frontal-parietal brain regions
  • Corpus callosum
  • Limbic system
    This includes:²⁹
    • Corpus mamillare
      • Memory formation, in the context of the Papez neuron circle
      • Sexual functions
    • Cingulate gyrus
      • Vegetative functions
      • Psychomotor and locomotor drive
    • Parahippocampal gyrus
      • Primarily transmits information from the limbic system to the hippocampus
      • Memory formation
    • Hippocampus
      • Memory formation
      • Vegetative and emotional functions
    • Amygdala
      • Storage of emotionally moving memory content
      • Vegetative and sexual functions

5. Myelination¶

One study found no differences in ADHD in terms of myelin content throughout the brain.³⁰
ADHD correlated with

• a higher mean myelin volume fraction in
  • bilateral inner capsule
  • outer capsule
  • Corona radiata
  • Corpus callosum
  • left tapetum
  • left superior fronto-occipital fascia
  • right cingulum

6. Cerebral blood flow (CBF)¶

A meta-analysis of k = 20 studies with n = 2232 subjects found that in people with ADHD³¹

• in idle state
  • reduced CBF (hypoperfusion)
    • in the right orbitofrontal gyrus
    • in the temporal cortex
    • in the basal ganglia
    • in the putamen
  • increased CBF (hyperperfusion)
    • in the frontal lobe
    • in the left postcentral gyrus
    • in the occipital lobe
• for cognitive tasks
  • increased CBF (hyperperfusion)
    • in frontal areas
    • in temporal regions
    • in the cingulate cortex
    • in the Precuneus
• after administration of methylphenidate
  • Increase in CBF
    • in striatal and posterior periventricular regions
    • in the right thalamus
    • in the precentral gyrus

In adults with ADHD and comorbid nociplastic pain, treatment with methylphenidate or atomoxetine reduced cerebral blood flow:³²

• in the Precuneus
• in the insular gyrus
• in the thalamus

Individual studies found changes in cerebral blood flow in ADHD:

• significantly reduced (hypoperfusion)
  • in the large quiescent state networks³³
    e.g. ventral attention network, somatomotor network, limbic network
  • in subcortical regions³³
  • in the orbitofrontal cortex³⁴
  • in the middle temporal gyrus in the right hemisphere³⁴

Increased cerebral blood flow (hyperperfusion) was found in contrast

• in the dorsomedial prefrontal PFC³⁴
• in the somatosensory area on both sides³⁴

Treatment with methylphenidate³⁴

• reduced hyperperfusion in the somatosensory area
• caused reduced blood flow in the right striatum
• increased CBF in the superior prefrontal area
• reduced CBF in the ventral higher visual areas on both sides

Hypoperfusion correlated with inattention or full ADHD symptoms:³³

• in the left putamen/global pallidum
• in the left amygdala
• in the left hippocampus

Adults with ADHD were found to have weaker negative functional connectivity between the left amygdala and the bilateral supplementary motor area, the bilateral superior frontal gyrus and the left medial frontal gyrus.³³

Children with ADHD were found to have³⁵

• no difference in CBF at the age of 6-7 years
• significantly lower CBF in the left postcentral gyrus and in the left middle frontal gyrus at the age of 8 to 9 years
• a significantly lower CBF in the left upper occipital region at the age of 10 to 12 years