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Does central nervous system dysfunction underlie patellofemoral pain in young females? Examining brain functional connectivity in association with patient‐reported outcomes

Patellofemoral pain (PFP) refers to significant retro‐ or peri‐patellar pain of the knee that is not directly associated with an obvious structural abnormality. PFP is a highly prevalent knee disorder (>20% of population). Females are 2–10 times more likely to develop PFP than males, and PFP detrimentally afflicts those who are physically active. Traditional and contemporary treatment approaches for patients with PFP have been generally unsuccessful at long‐term pain reduction or full restoration of physical functioning.

The studies in this area may overlook the complex central nervous system (CNS) processes that modulate the interaction of pain and sensorimotor control for those with movement dysfunction. Single‐pulse transcranialmagnetic stimulation (TMS) applied to the primary motor cortex (M1) demonstrated overlapping M1 cortical representations and a reduction in discrete cortical peaks of the rectus femoris, vastus lateralis, and vastus medialis musculature in patients with PFP compared with healthy controls. Patients with PFP also demonstratecomplex alterations to pro‐ and anti‐nociceptive pain mechanisms, including heightened sensitivity in response to pain or “hyperalgesia,” impaired conditioned pain modulation (CPM), and facilitated temporal summations of pain. These current findings indicate patients with PFP have centrally facilitated pain processing and responsiveness that contribute to treatment outcomes. However, the CNS mechanisms that propagate central pain sensitivity in patients with PFP remain largely unknown.

Methods capable of evaluating CNS functioning more directly, such as brain functional magnetic resonance imaging (fMRI), are warranted to enhance the current mechanistic understanding of PFP. One established fMRI technique quantifies temporal coherences of blood oxygen level‐dependent (BOLD) signals between spatially distinct brain regions, known as “functional connectivity”. Functional connectivity at rest provides stable or baseline indicators of brain function, as it generally reflects a history of spatially distinct brain regions “co‐activating” during active movement.

In this study, the authors compared functional connectivity between a population of young females with PFP and those with no knee pain (controls). The authors used literature to support the selection of a few regions to serve as “seeds” to evaluate their connectivity with all other brain voxels (seed‐to‐voxel analyses). Based on the literature findings, they created six seeds likely involved in both pain processing and psychological/sensorimotor functioning for patients with PFP. Specifically, they focused on the thalamus, primary somatosensory cortex (S1), cingulate cortex (anterior [ACC] and posterior divisions [PCC]), amygdala, and cerebellum. The primary purpose of this study was to determine differences in functional connectivity between patients with PFP and matched controls for the selected brain regions. A secondary objective of this study was to determine the degree to which perceived disability, movement dysfunction, and kinesiophobia were related to altered functional connectivity of the selected brain regions.

Young female patients with PFP (n=15; 14.3±3.2 years; BMI = 22.78±4.0) participated in this case–controlstudy. Each patient with PFP was matched with two control participants, based on age and BMI. Participants completed resting‐state fMRI and patient‐reported outcome measures. To assess differences in brain functional connectivity between the patients with PFP and controls, seed‐to‐voxel analyses were conducted for all six seeds.

There were no group differences in functional connectivity between the patients with PFP and controls for the bilateral ACC seed (all p > 0.05). Patients with PFP exhibited less connectivity between the bilateral thalamus seed and one cluster in the bilateral ACC compared with controls (p = 0.011).

There were no group differences in connectivity between the patients with PFP and controls for the bilateral amygdala seed (all p > 0.05). However, in patients with PFP, greater pain‐related disability was related to greater connectivity between the bilateral amygdala seed and clusters in the left (L) postcentral gyrus (S1; p = 0.041) and right (R) supramarginal gyrus (p = 0.041). Greater movement-related dysfunction scores were related to greater connectivity between the bilateral amygdala seed and clusters in the L lingual gyrus (p < 0.001) and L intracalcarine cortex (p < 0.001). Greater fear of pain/movement) was related to greater connectivity between the bilateral amygdala seed and one cluster in the bilateral precuneus (p = 0.03).

Patients with PFP exhibited greater connectivity between the bilateral S1 seed and clusters in the R (p = 0.006) and L precentral gyri (M1; p = 0.008) compared with controls. They also exhibited lower connectivity between the bilateral cerebellum VI seed and clusters in the bilateral ACC (p = 0.01) and L insular (p = 0.019) compared with controls. Less connectivity between the bilateral PCC seed and one cluster in the R hippocampus was observed in patients with PFP compared to controls (p = 0.020).

The findings indicate that chronic pain, less perceived function, and greater perceived movement‐related fear/disability in patients with PFP may contribute to residual CNS alterations in functional brain connectivity. The between‐group findings show that patients with PFP exhibit widespread CNS alterations throughout regions important for pain processing/sensitization, psychological functioning, and sensorimotor integration more broadly. Standard rehabilitation approaches may not be optimized to counteract this neural connectivity, but adopting principles from motor learning has the potential to provide means to subtly influence neural activity

Source:

Diekfuss JA et al. (2021) Does central nervous system dysfunction underlie patellofemoral pain in young females? Examining brain functional connectivity in association with patientreported outcomes. J Orthop Res. 2021; 114.

Download link to paper: Here

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