Diez I, Ortiz-Terán L, Williams B, Jalilianhasanpour R, Ospina JP, Dickerson BC, Keshavan MS, LaFrance WC Jr, Sepulcre J, Perez DL. Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder. J Neurol Neurosurg Psychiatry. 2019 Mar 8. pii: jnnp-2018-319657. doi:10.1136/jnnp-2018-319657. [Epub ahead of print]
Some individuals with functional neurological disorder (FND) exhibit motor and affective disturbances, along with limbic hyper-reactivity and enhanced motor-limbic connectivity. Given that the multimodal integration network (insula, dorsal cingulate, temporoparietal junction (TPJ)) is implicated in convergent sensorimotor, affective and interoceptive processing, we hypothesised that patients with FND would exhibit altered motor and amygdalar resting-state propagation to this network. Patient-reported symptom severity and clinical outcome were also hypothesised to map onto multimodal integration areas.
Between-group differences in primary motor and amygdalar nuclei (laterobasal, centromedial) were examined using graph-theory stepwise functional connectivity (SFC) in 30 patients with motor FND compared with 30 healthy controls. Within-group analyses correlated functional propagation profiles with symptom severity and prospectively collected 6-month outcomes as measured by the Screening for Somatoform Symptoms Conversion Disorder subscale and Patient Health Questionnaire-15 composite score. Findings were clusterwise corrected for multiple comparisons.
Compared with controls, patients with FND exhibited increased SFC from motor regions to the bilateral posterior insula, TPJ, middle cingulate cortex and putamen. From the right laterobasal amygdala, the FND cohort showed enhanced connectivity to the left anterior insula, periaqueductal grey and hypothalamus among other areas. In within-group analyses, symptom severity correlated with enhanced SFC from the left anterior insula to the right anterior insula and TPJ; increased SFC from the left centromedial amygdala to the right anterior insula correlated with clinical improvement. Within-group associations held controlling for depression, anxiety and antidepressant use.
These neuroimaging findings suggest potential candidate neurocircuit pathways in the pathophysiology of FND.
"The mechanistic understanding of functional neurological disorder is in its infancy compared to other major neurologic or psychiatric conditions," says David Perez, MD, MMsc, of the MGH Departments of Neurology and Psychiatry, who leads the hospital's Functional Neurology Research Group, and is co-senior author of the current paper. "Our previous work found that structural changes in the insula—a brain structure that may be involved with self- and emotional awareness—correlated with physical disability in patients with functional neurological disorder. In this study we also were able to demonstrate a similar correlation of symptom severity with the flow of information between the left insula and other areas involved in awareness and bodily perceptual processing."
Functional neurological disorder (FND) involves symptoms such as tremors, weakness, seizures, and trouble walking that cannot be explained by traditional neurologic diagnoses. Previously believed to be the result of patients' converting emotional distress into physical symptoms—leading to the name 'conversion disorder' - FND has been shown by Perez's team and others to involve altered activity of brain structures involved with emotional processing and motor control. The current study was designed to investigate precisely how communication is changed between these structures in patients with FND and how patterns of brain activity relate to symptom severity.
To do so, the research team used an MRI-based approach developed by co-senior author Jorge Sepulcre, MD, Ph.D., DMSc, of the Gordon Center for Medical Imaging at MGH, to examine the functional connectivity—a measure of the coupling and coordination of neural signals—between brain structures involved in processing emotional or motor signals and a set of areas called the multimodal integration network, which Sepulcre and others have previously characterized as integrating sensorimotor, cognitive and emotional information.
The results of the study, which compared 30 patients with FND to 30 healthy controls, indicated increased connectivity between motor regions and several portions of the multimodal integration network among FND patients. Not only did symptom severity correlate with increased connectivity between specific network structures, but the study revealed—for the first time—that increased coupling between the insula and the amygdala, a structure key to emotional processing, correlated with improved response to treatment.
"While this is an early study that warrants replication, it is an important advance in bridging the gap between understanding the biology of FND and improving the lives of patients with this disorder," says Perez, an assistant professor of Neurology at Harvard Medical School (HMS). "As a next step, we are planning to collect brain scan data taken before and after patients are treated, which should allow us to more closely examine structural and functional brain changes that relate to clinical improvement."
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