In individuals with functional neurological disorder (FND), the brain generally appears structurally normal on clinical MRI scans but functions incorrectly (akin to a computer software crashing), resulting in patients experiencing symptoms including limb weakness, tremor, gait abnormalities and non-epileptic seizures.
In some cases, childhood maltreatment may have been a contributing factor, yet links between risk factors such as childhood abuse and brain mechanisms for the development of FND remain poorly understood.
In a new study published in Molecular Psychiatry, researchers led by investigators at Massachusetts General Hospital (MGH) examined the brains of individuals who experienced early-life trauma, some with FND and others without the condition.
The findings may provide a better understanding of what happens in the brains of some patients with FND, as well as those with various other trauma-related brain disorders.
In the study of 30 adults with FND and 21 individuals whose clinical depression diagnoses served as controls, some of the participants in both groups had experienced early-life maltreatment, as determined through questionnaires.
In FND patients only, differences in the severity of childhood physical abuse correlated with differences in connections between certain regions of the brain–for example, between the limbic regions which control emotions, arousal and survival instincts among other functions, and the primary motor cortex which is involved in voluntary movements.
“Motor and limbic circuits were more strongly interconnected in individuals with FND reporting a greater severity of childhood physical abuse,” explained lead author Ibai Diez, PhD, a senior research fellow in Neurology and Radiology at MGH.
This finding may lead to potentially important insights on the plastic brain mechanisms involved in promoting increased cross-talk between motor control circuits and emotion processing circuits.
In FND patients only, differences in the severity of childhood physical abuse correlated with differences in connections between certain regions of the brain–for example, between the limbic regions which control emotions, arousal and survival instincts among other functions, and the primary motor cortex which is involved in voluntary movements.
In additional assessments, investigators examined how the expression of genes in a publicly available data set from the Allen Institute related to brain areas showing prominent plastic effects correlated to the degree of early-life physical abuse in patients with FND.
As background, some genes in the literature have been shown to increase risk for developing brain disorders after experiencing early-life maltreatment.
The researchers found that brain areas showing prominent functional re-organization in patients with FND were the same brain areas highly expressing genes involved in neuroplasticity and nervous system development.
“Our study has potential implications regarding our understanding of brain-trauma relationships not only in patients with FND but also across the greater spectrum of trauma-related brain disorders,” said senior author David Perez, MD, MMSc, director of the MGH FND Clinical and Research Programs.
Perez stressed that although childhood maltreatment may be a risk factor for the development of FND in some individuals, there are many social, environmental, and biological factors that likely influence the development of FND later in life.
“More work is needed to understand how the brain mechanisms underlying FND in those without prominent childhood maltreatment may be the same or different as those individuals with FND with a high burden of childhood adversity,” he said.
Funding: The research was the result of a collaboration between the MGH Functional Neurology Research Group led by Perez, the laboratory of Jorge Sepulcre, MD, PhD, in MGH’s Gordon Center for Medical Imaging, Gregory Fricchione MD of the Benson-Henry Institute, the laboratory of Erin Dunn PhD, and Timothy Nicholson MD, PhD, of King’s College London.
Functional neurological (conversion) disorder (FND) is a complex condition at the interface of neurology and psychiatry (Trimble and Reynolds, 2016).
Prior to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) revised criteria (American Psychiatric Association, 2013; Stone et al., 2010a), FND for neurologists was largely a diagnosis for individuals with “medically unexplained” sensorimotor neurologic symptoms.
As such, patients with FND were marginalized for much of the 20th century, with limited clinical and neuroscientific interest (Keynejad et al., 2017; Stone et al., 2008).
By contrast, founders of modern neurology and psychiatry were immensely intrigued by FND. Charcot theorized that functional motor symptoms were due to a “dynamic lesion” adversely impacting motor pathways (Bogousslavsky, 2014).
Freud shifted the focus to the unconscious mind and theorized that psychological conflicts were “converted” to bodily symptoms to relieve distress (Breuer and Freud, 1956). The French psychologist Janet proposed a role for dissociation framed as a “retraction of the field of personal consciousness” (Janet, 1907).
Recently, there is renewed interest in FND, catalyzed by the DSM-5 diagnostic criteria and pathophysiology-based research (Carson et al., 2012). Neurologically, emphasis is now given to identifying examination signs and semiologic features specific for FND (Avbersek and Sisodiya, 2010; Daum et al., 2014).
Modern biopsychosocial formulations for FND incorporate the spectrum of predisposing vulnerabilities, acute precipitants, and perpetuating factors (Keynejad et al., 2018; Pick et al., 2018; Reuber, 2009).
The “software” vs. “hardware” analogy is a useful concept when discussing the diagnosis of FND with patients (Carson et al., 2016).
According to this framing, the hardware (i.e. brain) lacks relevant structural abnormalities, however, the software (i.e. how the brain works) has a glitch that manifests in functional neurological symptoms.
This framework is supported by the preservation of brain structure on clinical inspection of magnetic resonance imaging (MRI) scans at the macroscopic level.
In parallel, there has been considerable advance using task and resting-state functional neuroimaging to delineate the emerging neurobiology of FND, summarized in several reviews and meta-analyses (Boeckle et al., 2016a; McSweeney et al., 2017; Perez et al., 2015b; Voon et al., 2016). Major themes across functional neuroimaging studies include:
(1) heightened amygdalar reactivity to affectively valenced stimuli (Aybek et al., 2015; Aybek et al., 2014b; Hassa et al., 2017; Kanaan et al., 2007; Morris et al., 2017; Voon et al., 2010a);
(2) increased limbic/paralimbic-sensorimotor connectivity (Espay et al., 2018b; Li et al., 2015a; Li et al., 2015b; Szaflarski et al., 2018; van der Kruijs et al., 2012, 2014; Voon et al., 2010a);
(3) right temporoparietal junction/inferior parietal lobule hypoactivation and altered connectivity with sensorimotor cortices (Baek et al., 2017; Maurer et al., 2016; Voon et al., 2010b);
(4) attentional dysregulation (Ghaffar et al., 2006; Mailis-Gagnon et al., 2003; Vuilleumier et al., 2001); and (5) deficits in motor planning (Voon et al., 2011), intention (de Lange et al., 2010; Spence et al., 2000), execution (Schrag et al., 2013; Stone et al., 2007) or inhibition (Cojan et al., 2009; Marshall et al., 1997; Tiihonen et al., 1995).
Other abnormalities include implicit attentional biases (Pick et al., 2018), perceptual-cognitive inferences (Edwards et al., 2012), and mnemonic contributions to metacognitive processes disrupting subjective experience (Bègue et al., 2018b).
While the framing of FND as a “software” problem is well-received, this conceptualization may require more nuanced considerations. Notably, the shift from “psychogenic” to “functional” neurological disorders was proposed to eliminate false mind versus brain dichotomies (Edwards et al., 2014); similarly, structure-function relationships are well-recognized to be closely intertwined.
Emerging structural neuroimaging findings point towards a parallel “hardware” related neurobiology in some FND populations, further bridging the divide between neurologic and psychiatric conceptualizations (Perez et al., 2018a).
In addition, FND frequently co-exists clinically with the somatic symptom disorders (SSD) as largely defined in DSM-IV (somatization disorder, somatoform pain disorder, and undifferentiated somatoform disorder) (Kozlowska et al., 2018; Sar et al., 2004; Stone et al., 2010b); a few FND studies reported comorbidities rates with somatoform disorders above 50% (Bowman and Markand, 1996; Sar et al., 2004).
The SSD category in the DSM-5 was designed to consolidate the DSM-IV diagnostic categories of somatization disorder, somatoform pain disorder, and undifferentiated somatoform disorder, although this reconceptualization has markedly different criteria based on cognitive-affective and behavioral aspects and is more explicit about including patients with defined medical conditions (Dimsdale et al., 2013).
No studies have explicitly examined the overlap between FND and DSM-5 SSD, and we are unaware of any structural neuroimaging studies of DSM-5 SSD. Therefore, for the purposes of this article we use the term SSD to describe the somatic symptom disorders in DSM-IV. We acknowledge that this is not a one to one translation (see limitation section).
The explicit co-occurrence of FND and SSD was previously codified in part by the DSM-IV somatization disorder diagnostic category that encompassed individuals with functional neurological symptoms and other prominent somatic symptoms. FND and SSD share predisposing vulnerabilities (e.g. female predominance, high rates of depression-anxiety and adverse life event burden (Guz et al., 2004; Paras et al., 2009; Taylor, 2003)) further raising the possibility of a partially overlapping biology. Comorbid somatic symptoms in patients with FND also negatively impact healthcare utilization and prognosis (Ettinger et al., 1999; Glass et al., 2018; Ibrahim et al., 2009; Salinsky et al., 2016).
Reviews and meta-analyses have summarized the functional neurobiology of SSD compared to healthy controls (Boeckle et al., 2016b; Landa et al., 2012; Perez et al., 2015a), which includes:
(1) increased limbic, paralimbic (insula, parahippocampal), and striato-thalamic activity during noxious tactile stimuli (Gundel et al., 2008; Luo et al., 2016; Stoeter et al., 2007);
(2) decreased engagement of regulatory prefrontal regions during sensory and affective processing (Gundel et al., 2008; Noll-Hussong et al., 2013);
(3) and sensorimotor, salience and default mode network resting-state alterations (Hakala et al., 2002; Karibe et al., 2010; Li et al., 2016; Zhao et al., 2017).
To aid the early-phase incorporation of structural neuroimaging findings in the development of biological models for FND and other functional somatic disorders, we used a transdiagnostic approach to conduct a systematic review and critically appraise the structural MRI literature in FND and SSD.
We contextualized the structural neuroimaging literature within the neurobiology of stress-related neuroplasticity, gender differences, psychiatric comorbidities, and the greater spectrum of functional somatic disorders. Lastly, future directions were outlined that may help accelerate the characterization of the pathophysiology of these enigmatic conditions.
Source:
Mass General
