Altered paired associative stimulation‐induced plasticity in NMDAR encephalitis

Abstract

ObjectiveTo determine whether neurophysiological mechanisms indicating cortical excitability, long‐term potentiation (LTP)‐like plasticity, GABAergic and glutamatergic function are altered in patients with anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis and whether they can be helpful as markers of diagnostic assessment, disease progression, and potentially therapy response.MethodsNeurophysiological characterizations of patients with NMDAR encephalitis (n = 34, mean age: 28 ± 11 years; 30 females) and age/gender‐matched healthy controls (n = 27, 28.5 ± 10 years; 25 females) were performed using transcranial magnetic stimulation‐derived protocols including resting motor threshold, recruitment curve, intracortical facilitation, short intracortical inhibition, and cortical silent period. Paired associative stimulation (PAS) was applied to assess LTP‐like mechanisms which are mediated through NMDAR. Moreover, resting state functional connectivity was determined using functional magnetic resonance imaging.Results PAS‐induced plasticity differed significantly between groups (P = 0.0056). Cortical excitability, as assessed via motor‐evoked potentials after PAS, decreased in patients, whereas it increased in controls indicating malfunctioning of NMDAR in encephalitis patients. Lower PAS‐induced plasticity significantly correlated with the modified Rankin Scale (mRS) (r = −0.41; P = 0.0031) and was correlated with lower functional connectivity within the motor network in NMDAR encephalitis patients (P < 0.001, uncorrected). Other neurophysiological parameters were not significantly different between groups. Follow‐up assessments were available in six patients and demonstrated parallel improvement of PAS‐induced plasticity and mRS.InterpretationAssessment of PAS‐induced plasticity may help to determine NMDAR dysfunction and disease severity in NMDAR encephalitis, and might even aid as a sensitive, noninvasive, and well‐tolerated “electrophysiological biomarker” to monitor therapy response in the future.Clinical Trial RegistrationClinicalTrials.gov: Identifier: NCT01865578

Aberrant multimodal brain networks in patients with anti‐NMDA receptor encephalitis

“…We also observed abnormal nodal centrality as characterized by both decreases and increases in the patients. This suggests the co‐existence of pathological impairments and compensatory adaptions in anti‐NMDAR encephalitis 34 . Specifically, lower nodal efficiency was observed in the amygdala of structural brain networks (FN weighted) in the patients, implying declined efficiency of the amygdala in the coordination with other regions.…”

Functional Connectivity Changes of Anti‐N‐Methyl‐D‐Aspartate Receptor Encephalitis: A Graph‐Theoretic and Topology‐Based Study

“…We also observed lymph node features in the abnormal thalamus characterized by a decrease in centrality and an increase in efficiency of the lymph nodes in patients. This indicates that pathological damage and compensatory adaptation coexist in anti-NMDAR encephalitis (Volz et al 2016 ). Reduced FC and lymph node centrality in the thalamus could explain the emotional dysfunction seen in NMDAR encephalitis.…”

A comprehensive review of transcranial magnetic stimulation in secondary dementia

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“…Cortical excitability after PAS was found to be decreased in anti-NMDA receptor encephalitis ( Volz et al, 2016 ). Also, the lower PAS-induced plasticity significantly correlated with the modified Rankin Scale and with a lower functional connectivity within the motor network.…”

“…Follow-up assessments, available in 6 patients, demonstrated a parallel improvement of PAS-induced plasticity and functional status. These findings indicate that neurophysiological mechanisms, including cortical excitability, LTP-like plasticity, GABAergic and glutamatergic functioning, are altered in patients with anti-NMDA receptor encephalitis and they can be helpful in diagnostic, prognostic, and response to therapy ( Volz et al, 2016 ).…”