Abnormally high levels of limbic glutamate may be at the root of unexplained functional motor symptoms (FMS) that previously have been attributed to “hysteria.”
Researches used magnetic resonance spectroscopy (MRS) to evaluate N-acetylaspartate (NAA) levels; myo-inositol (MI) levels; choline (Cho) levels; the sum of glutamate and glutamine (Glx); and creatine (Cr) content in two brain regions of patients with FMS and compared those results to results obtained from healthy control persons.
They found increased levels of Glx/Cr content in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) in patients with FMS but normal levels in the occipital cortex (OCC) compared to control persons.
These increased levels correlated with FMS-related alexithymia and anxiety as well as symptom severity.
“We assessed by MRS patients by glutamate and glutamine in a group of patients with FMS and in a group of healthy age- and sex-matched controls, testing the limbic areas of the cerebral cortex and, as a control region, the visual cortex and also clinically through a number of clinical scales,” senior author Alberto Priori, MD, PhD, of the Aldo Revelli Research Center at the University of Milan, Italy, told Medscape Medical News.
“We found that glutamate is abnormally increased in the limbic but not in the visual cortex of patients and that the increase correlated with the severity of motor and psychological disturbances,” he added.
Frequent, Still Mysterious
“Functional neurological disorders are very difficult to be treated and very expensive for the national health systems worldwide,” said Priori, whose research group “deals with the biology of this frequent but still mysterious condition.”
Functional neurologic symptoms are “what historically was called ‘hysteria,’ a condition known for a long time in the medical literature and thought to be linked to unresolved conflicts and purely psychological problems,” he continued.
He noted that Sigmund Freud developed psychoanalysis “mostly to resolve functional problems.”
For several years, Priori’s group has focused on clarifying the biological mechanisms underlying these disturbances. They “decided as a first step to study the brain neurochemistry of our patients with a noninvasive technique,” he said.
They chose to study the limbic system because it is thought to be involved in FMS. They used MRS to quantify several brain metabolites: NAA, which is a neural and axonal integrity marker; MI, an inflammatory marker; and Cho, which is involved in cell membrane synthesis and degradation.
They also studied glutamate — the major excitatory neurotransmitter — and Glx and Cr in the ACC/mPFC and in the OCC.
The researchers also examined correlations between limbic metabolite content and FMS-related clinical features: motor symptom severity, alexithymia, anxiety, depression, and quality of life in 10 patients with FMS and 10 age- and sex-matched control persons (mean [SD] age, 47.10 years [17.00 years] and 44.3 years [12.85 years], respectively).
Participants were required to complete the Mini–Mental State Examination, the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), the 20-Item Toronto Alexithymia Scale (TAS-20), and the EuroQol 5D (EQ-5D).
Participants had to be free of any other neurologic disorders, including dementia, and medical diseases and to have no overlap between functional disorders and other movement disorders.
Control participants had normal rating scores for psychopathology. Two case patients had major depressive disorders, and one had panic disorder.
Three case patients were taking selective serotonin reuptake inhibitors, and four were taking benzodiazepines, which they stopped taking 5 days before undergoing MRS.
Glx/Cr was found on MRS to be higher in case patients with FMS than in healthy control persons in the ACC/mPFC but not in the OCC, as determined on the basis of a two-way ANOVA calculation that showed a significant interaction between the factors “brain site” and “group” (P = .001).
Moreover, post hoc analysis showed an increase in Glx/Cr in the ACC/mPFC in case patients vs healthy control persons (mean ± SD: 1.52 ± 0.56, vs 0.677 ± 0.050, respectively; P = .0005).
These findings remained, even when HAM-D, HAM-A, and TAS-20 scores were entered as a covariate in the same model.
There were no differences between case patients and control persons with regard to NAA/Cr, Cho/Cr, or MI/Cr either in the ACC/mPFC or in the OCC.
When the researchers conducted a correlation analysis between Glx/Cr and psychological scales, they found that in the overall population, the Glx/Cr in the ACC/mPFC correlated with anxiety (HAM-A, ρ = 0.732; P = .003) and alexithymia (TAS-20, ρ = 0.432; P = .02).
In case patients, Glx/Cr content in the ACC/mPFC was also correlated with the severity of functional motor symptoms.
“Glutamate is the major excitatory neurotransmitter in the brain. There are two hypotheses that could explain our findings. Firstly, the increased glutamate could be the prime mover creating an abnormal excitatory output from the limbic to the motor areas of the cerebral cortex.
“Alternatively, increase glutamate could be secondary to downregluation of its receptors or to impaired activity of its degrading enzymes,” Priori said.
He noted that his group is currently conducting further research that “will better clarify this issue.”
Commenting on the study for Medscape Medical News, Carine Maurer, MD, PhD, assistant professor of neurology and associated director, Medical Scientist Training Program, Stony Brook University School of Medicine, New York, who was not involved with the study, noted that the sample size is “quite small and findings will need to be replicated in larger studies.”
Nevertheless, the study “provides intriguing evidence for abnormally increased paralimbic glutamate/glutamine in patients with FMD, as measured by MRS,” she said.
The study augments previous research that suggests there are neurobiological differences in patients with FMD, including the presence of group-level differences in functional and structural imaging findings.
Although the authors report that metabolic changes correlated with severity of motor symptoms, “this finding needs to be interpreted cautiously, given limitations in scales used to assess FMD symptom severity,” she said.
Nevertheless, “for the practicing clinician, from a practical point of view, this helps with conceptualization of the disorder and patient education,” she said.
Moreover, she said, the findings have “intriguing implications for future research and suggests that drugs targeting the NMDA [N-methyl-D-aspartate] receptor may be promising as future pharmacological targets.”
“Unexplained functional neurological symptoms, historically known as hysteria, are recognized a neurochemical abnormality that could be targeted by the specific treatments for this condition,” Priori said.
Such treatments include psychotherapy, rehabilitation, and drugs, he said.
He noted that several classes of drugs currently available for other indications can influence the glutamatergic system “and could therefore be useful for these patients.”
The study was partly supported by the Aldo Ravelli Research Center on Neurotechnology and Experimental Brain Therapeutics at the Department of Health Sciences, University of Milan, Italy. Priori and Maurer have disclosed no relevant financial relationships. The other authors’ disclosures are listed in the original article.
Neurology. Published online June 5, 2019. Abstract