Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain

Naylor, Brooke; Hesam‐Shariati, Negin; McAuley, James H.; Boag, Simon; Newton‐John, Toby; Rae, Caroline; Gustin, Sylvia M.

doi:10.3389/fneur.2019.01110

Cited by 30 publications

(12 citation statements)

References 122 publications

(145 reference statements)

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“…The decrease in mPFC glutamate is consistent with current chronic pain literature. It aligns with our previous findings in a smaller sample size in individuals with chronic pain (Naylor et al., 2019). Reduced mPFC glutamate has also been demonstrated in animal research (Kelly et al, 2016; Palazzo et al., 2016), where glutamate has been observed to initially elevate during the acute phase of pain before decreasing when progressing to chronic pain (Guida et al., 2015).…”

Section: Discussionsupporting

confidence: 93%

“…Guida et al., (2015) suggested that, following injury, during the acute pain phase, there is an initial rise in glutamate that is followed by a reduction during its progression to chronicity. In line with this suggestion, we have recently observed a decrease in glutamate in the mPFC of people with chronic pain, which was associated with emotional dysregulation (Naylor et al., 2019). A decline in GABA + has been revealed in the rat ACC (Narita et al., 2011; Yamashita et al., 2014), which is a subregion of the mPFC in the rodent model (Öngür & Price, 2000).…”

Section: Introductionsupporting

confidence: 68%

“… b Individual has participated in Naylor and colleagues in regard to the proton spectroscopy (Naylor et al., 2019). …”

Section: Resultsmentioning

confidence: 99%

“…Twenty‐four subjects with chronic pain (14 males; mean [± SD ] age 52 ± 7.6 years) and twenty‐four age‐ and sex‐matched controls without pain (14 males; mean [± SD age 49 ± 7.2 years) were recruited for the study. Notably, 17 people with chronic pain and 18 healthy controls overlap with the study cohort in Naylor and colleagues in regard to the proton spectroscopy (Naylor et al., 2019) (Table 2). Chronic pain subjects had conditions diagnosed according to the following criteria: the International Association for the Study of Pain SCI Pain Taxonomy for below‐level neuropathic pain after spinal cord injury (SCI) (Siddall et al., 2002) ( n = 14); the Liverpool Criteria for atypical trigeminal neuralgia (ATN) ( n = 1), trigeminal neuropathy (TNP) ( n = 2) and postherpetic neuralgia (Nurmikko & Eldridge, 2001) ( n = 1); and the Research Diagnostic Criteria for temporomandibular disorder (TMD) associated with myofascial pain syndrome (Dworkin, 1992) ( n = 6).…”

Section: Methodsmentioning

confidence: 99%

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Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain

Kang

Hesam‐Shariati

McAuley

et al. 2021

European Journal of Pain

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Background Growing evidence indicates a link between changes in the medial prefrontal cortex and the pathophysiology of chronic pain. In particular, chronic pain is associated with altered medial prefrontal anatomy and biochemistry. Due to the comorbid affective disorders seen across all pain conditions, the medial prefrontal cortex is a region of significance as it is involved in emotional processing. We have recently reported that a decrease in medial prefrontal N‐acetylaspartate and glutamate is associated with increased emotional dysregulation, indicating there are neurotransmitter imbalances in chronic pain. Therefore, we compared medial prefrontal neurochemistry in 24 people with chronic pain conditions to 24 age and sex‐matched healthy controls with no history of chronic pain. Method GABA‐edited MEGA‐PRESS was used to measure GABA+ levels, and short TE PRESS was used to measure glutamate levels in the medial prefrontal cortex. Psychometric measures regarding pain intensity a week before scanning, during the scan and the total duration of chronic pain, were also recorded and compared to measured GABA+ and glutamate levels. Results This study reveals that the presence of chronic pain is associated with significant decreases in medial prefrontal GABA+ and glutamate. These findings support the hypothesis that chronic pain is associated with altered medial prefrontal biochemistry. Conclusion The dysregulation of glutamatergic and GABAergic neurotransmitter systems supports a model of disinhibition of chronic pain, which may play a key role in both the experience of persistent pain and its associated affective disturbances. Significance This study reveals a significant reduction in γ‐aminobutyric acid (GABA+) and glutamate within the medial prefrontal cortex in chronic pain sufferers. While the current findings should be considered with reference to a small sample size, the disruption to normal excitatory and inhibitory medial prefrontal cortex function may be key in the development and maintenance of chronic pain and comorbid mental health disorders.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionsupporting

confidence: 68%

“… b Individual has participated in Naylor and colleagues in regard to the proton spectroscopy (Naylor et al., 2019). …”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain

Kang

Hesam‐Shariati

McAuley

et al. 2021

European Journal of Pain

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“…| 2071et al, 2010Naylor et al, 2019). Remarkably, chronic pain is correlated with an increased level of inflammation, such as Creactive protein (CRP) levels (Parkitny et al, 2013) and CRP was associated with cognitive decline and Alzheimer's disease (Dunn et al, 2005;.…”

Section: Discussionmentioning

confidence: 99%

Persistent moderate to severe pain and long‐term cognitive decline

Rong

Zhang

Zheng

et al. 2021

European Journal of Pain

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Background: The longitudinal association between persistent moderate to severe pain and subsequent long-term cognitive decline remains inconclusive. Methods: Study population came from the English Longitudinal Study of Ageing, an ongoing prospective and nationally representative cohort of community-dwelling adults aged ≥50 years in England. At waves 1 (2002/2003) and 2 (2004/2005) of the study, pain severity was measured based on pain intensity scores ranged from 0 to 10. We defined moderate to severe pain as pain intensity scores ≥5 points. Persistent moderate to severe pain was defined as participants reported moderate to severe pain at both waves 1 and 2. Standardized global cognitive Z scores derived from verbal memory, temporal orientation and semantic fluency were used as the primary outcome. Results: A total of 6,869 individuals (3,896 women; mean age: 63.9 ± 9.5 years) who have accepted twice measurements of pain at waves 1 and 2 (baseline), and at least one reassessment of cognitive function at waves 3 (2006/2007) to 8 (2016/2017), were included in this study. Each 5-point increase in the sum of pain intensity scores was associated with a faster rate of -0.009 (95% CI: -0.013 to -0.006, p < .001) in global cognitive Z scores. Compared with no pain group, persistent moderate to severe pain group was associated with a significantly faster decline rate of -0.031 SD/year (95% CI: -0.043 to -0.018), in global cognitive Z scores. The relationships of persistent moderate to severe pain with verbal memory, temporal orientation and semantic fluency were similar. Conclusion: Cognitive function should be monitored in individuals with persistent moderate to severe pain.

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The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults

Widegren,

Frick,

Hoppe

et al. 2024

Developmental Psychobiology

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During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self‐reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13–16 years) and adults (n = 39; 30–40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within‐group follow‐up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age‐group differences in gamma‐aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA‐ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age‐related differences in emotion processing.

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Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain

Cited by 30 publications

References 122 publications

Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain

Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain

Persistent moderate to severe pain and long‐term cognitive decline

The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults

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