An Integrated Approach Aids Functional Neurological Disorder Care and Research

Functional neurological disorder (FND), previously known as "hysteria" or "conversion disorder," is the second most common reason (after headache) that patients receive outpatient neurology consultations. Patients present with a variety of physical symptoms including seizures, tremor, difficulty walking and limb weakness. These physical symptoms do not neatly fit the description of any traditional neurologic condition.

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Massachusetts General Hospital clinician-scientists are leveraging Mass General's Functional Neurological Disorders Treatment Program and Functional Neurology Research Group in tandem to better care for and understand the neurobiology of FND.

"FND has fallen through the cracks because, by its very nature, it lives at the intersection of neurology and psychiatry. It's gotten lost in that borderland," says David Perez, MD, MMSc, director of the FND Treatment Program and member in the Department of Neurology and Department of Psychiatry.

"Our clinical and research efforts are working to bring FND out of the shadows and into mainstream neuropsychiatric clinical care models," says Dr. Perez. "In the laboratory, we've provided early foundational support for a specific role of the salience network in the biology of FND. We look forward to our next challenge of characterizing biologically important subtypes."

A Transdiagnostic Approach to FND

Unlike some clinics that focus on one FND subtype, Mass General clinicians see patients across the motor spectrum, including psychogenic nonepileptic (dissociative) seizures, functional limb weakness and functional movement disorders. To address this gap, Dr. Perez and his colleagues developed an interdisciplinary FND program primarily based within the Department of Neurology with the aim to diagnose and provide evidence-based longitudinal care for patients with functional neurological disorder.

"We are among the leaders in the world in adopting this transdiagnostic approach," says Dr. Perez.

Patients receive an initial 90-minute neurologic and psychiatric evaluation. During the neurologic examination, clinicians check for symptoms recognized to be highly specific to FND including:

• Collapsing give-way weakness: Patients show full strength for a moment followed by limb collapse
• Tremor entrainment: Functional tremor movements can take on the rhythm of voluntary movements performed elsewhere in the body
• Seizure types: Certain features in clinical seizures are highly specific to the seizure subtype of functional neurological disorder. These features can include tight eye closure at onset or asynchronous side-to-side movements of the head and trunk

The FND team delivers diagnoses with clarity, empathy and validation, emphasizing that FND is real, common, brain-based and treatable. They also give patients educational material and leave time for questions before transitioning to treatment options.

"When they come to our clinic, their lives have often been significantly derailed by their illness. We pride ourselves on making good eye contact, listening to patient stories and gathering their natural histories. We focus on being present to help the patient feel heard," says Dr. Perez. "Then we can begin to collaborate on a road map to guide their recovery."

In addition to Dr. Perez, sub-specialty trained physicians within the Mass General FND program includes Christopher Stephen, MBChB, attending neurologist, Ann Hunt, DO, a comprehensive neurologist and Aneeta Saxena, MD, neurologist. "We are also proud to work closely with residents and fellows across neurology and psychiatry to train the next generation in caring for patients with FND," says Dr. Perez.

Individualized, Interdisciplinary FND Therapy

The diagnostic process lays the foundation for individualized FND treatment plans. Other core elements address motor symptoms through motor rehabilitation in physical therapy, occupational therapy and speech and language pathology, and utilize cognitive behavioral therapy as a primary treatment modality.

A psychotherapist delivers cognitive behavioral therapy during a weekly session. Patients are guided to explore the relationships between their physical symptoms, thoughts, behaviors, emotions and life factors. They also develop an awareness of triggers and their own physical warning signs, such as shortness of breath, heart racing and sweatiness. They use mind-body relaxation techniques, including diaphragmatic breathing, progressive muscle relaxation, mindfulness interventions and other distraction techniques, to break the cycle between early warning signs and worsening motor symptoms.

Monthly FND rounds involving a dual trained neurologist-psychiatrist, subspecialty-trained neurologists, psychologists, social workers, physical therapists, occupational therapists and speech and language pathologists maintain the interdisciplinary nature of their work.

"We're developing shared expertise," says Dr. Perez. "We are informed by psychotherapeutic principles and by rehab principles in how we think about patients and their treatment plans."

Understanding FND Through Novel Imaging

Dr. Perez's efforts in clinic have turned into important research opportunities as well. In the Functional Neurology Research Group, neuroimaging scientists, clinician-researchers and research assistants collaborate with other Mass General and Athinoula A. Martinos Center for Biomedical Imaging researchers to advance the understanding of the biology of FND. The Functional Neurology Research Group was one of the first labs to identify structural changes in the brains of FND patients.

This research group has recently shown how increased coupling across motor control and emotion processing brain areas in patients with FND relates to individual differences in risk factors, specifically adverse early-life events, reported in Molecular Psychiatry.

"The core basis of our research to date has been to identify biomarkers related to symptom severity and prognosis. We've identified a set of areas in the brain related to the salience network that appears to map onto patient-reported symptom severity." Dr. Perez says.

In a Journal of Neurology, Neurosurgery & Psychiatry study, Mass General investigators used structural neuroimaging to uncover gray matter differences in patients with FND. Looking at gray matter volume in the left anterior insula, they discovered that reductions in volume relate to patient-reported symptom severity in dose-dependent fashion. The sicker patients were, the larger the reduction in volume.

In a follow-up study in the Journal of Neurology, Neurosurgery and Psychiatry, investigators looked at patterns of resting-state connectivity using a novel stepwise functional connectivity approach developed by Jorge Sepulcre, MD, PhD, associate professor of Radiology. "This maps patterns of information flow from one pre-specified region to the rest of the brain," says Dr. Perez. "The pattern of information is related to the severity of symptoms being reported."

A recent study published in Psychological Medicine looking at white matter tracts showed disruptions in the microstructural integrity of seven fiber bundles in patients with FND compared to healthy controls:

• Stria terminalis/fornix
• Medial forebrain bundle
• Extreme capsule
• Uncinate fasciculus
• Cingulum bundle
• Corpus callosum
• Striatal to postcentral gyrus projections

Reduced integrity in limbic related tracts was associated with greater physical disability and illness duration. Dr. Perez's team was among the first groups to use diffusion tensor imaging (DTI) to examine white matter integrity in patients with FND. In this paper, Dr. Perez and Ibai Diez Palacio, PhD, research fellow in the Department of Neurology, developed a novel network analyses for DTI. They showed reduced integrity in limbic related tracts was associated with greater physical disability and illness duration.

"This approach not only identifies patterns of white matter abnormalities in the brain, it also relates those patterns to the implicated cortical and subcortical regions." relates Dr. Perez, who was senior author on the study. "Big picture, we're using the full range of multimodal neuroimaging approaches to advance our biological understanding of this common yet previously neglected condition."

Untangling the Mysteries of FND

In the future, Dr. Perez's team plans to further develop their treatment program so they can engage in non-imaging-based clinical trials. The lab is also interested in further exploring how risk factors—including adverse early-life events, difficulty putting emotions into words (alexithymia) and associations with other medical conditions, such as chronic pain disorders—map onto the biology.

"We have patients who come in unable to independently get out of a chair, who, following treatment, go back to work and school full-time," Dr. Perez says. "We have other patients who, despite our best efforts, continue to remain symptomatic. That's a striking range of treatment responses. In the future, we hope to more comprehensively investigate biomarkers of prognosis to advance that question as well."

Refer a patient to the Department of Neurology

Learn more about the Neurological Disorders (FND) Treatment Program