N-Methyl-D-Aspartate Receptor-Antibody Encephalitis Impairs Maintenance of Attention to Items in Working Memory

Discussion

NMDA receptors are important in WM storage (Lisman et al., 1998), but few causal studies in humans have asked what component mechanisms they support. Patients with NMDAR-antibody encephalitis have a selective reduction in postsynaptic NMDAR availability, including long into recovery (Galovic et al., 2023). We asked whether sustaining attention to items in WM and feature binding are affected by NMDAR hypofunction using a task that allowed modeling of error types. A striking finding was that in the long-delay condition, patients lacked the typical congruency benefit. In other words, patients had difficulty sustaining attention to prioritized items. Furthermore, patients make more misbinding errors than controls in congruent trials, suggesting they may struggle to remember associations, especially for prioritized information.

In a recent study of one-item WM, patients lacked interference from previous trials, which was explained by modeling in terms of diminished short-term potentiation caused by NMDAR hypofunction (Stein et al., 2020). Previous studies illustrated that incorporating prefrontal synaptic disinhibition (NMDAR hypofunction decreasing activation of GABA interneurons) into spatial WM modeling leads to reduced precision and greater distraction from near distractors (Murray et al., 2014). This may be one explanation for patients’ misbinding errors, as similar representations may be more difficult to differentiate. NMDAR antibodies lower receptor-mediated potentiation and currents (Hughes et al., 2010; X. Wang et al., 2019) which is evident in different cortical areas including the hippocampus (X. Wang et al., 2019) a region of high NMDAR density and a region often linked to memory (McHugh et al., 2007) particularly associative feature binding (Zokaei et al., 2019). It is possible that patients misbind more in the congruent condition as aberrant NMDAR-mediated synaptic function involved in paying attention to an item could make the representation more difficult to differentiate from the other item.

An important point to note is the possibility of potential hippocampal damage in patients which is difficult to completely distinguish from the direct effects of antibodies on NMDARs. There is a predominantly high expression of NMDARs in the hippocampus (Monaghan and Cotman, 1985) and, while we are interested in a receptor level deficit, it is likely that the deficit is partially localized to the hippocampus. MRI evidence suggests only a minority of patients may have long-term microstructural damage to the hippocampus (Finke et al., 2016: imaging mean 26.6 months after disease onset). Consistent with this, in our patient group the most recent MRI imaging of 8/10 patients posttreatment (average 26.1 months postdiagnosis) found the following: 6/10 had largely normal hippocampi; 2/10 had unreported scans—on assessment by the authors; one showed no hippocampal atrophy; and the other demonstrated mild hippocampal atrophy. Two out of 10 had no MRI imaging available. This indicates most of our patients had no substantial residual structural hippocampal damage following the acute phase of the disease.

Hebbian models of WM implicate NMDARs in binding features together to form neural “conjunctions,” potentially in the prefrontal cortex (Manohar et al., 2019). Sustained activity of neurons encoding these conjunctions may constitute attention to a specific item and is also dependent on NMDARs. Within such models, switching attention away from an item disrupts this persistent firing, but the synaptic weight changes remain. This allows unattended information to be reactivated, shifting attention back to that item. In our study, patients lost the congruency effect at long delays, with even decreased precision for the attended item. This indicates patients struggle to sustain attention on prioritized items over time. In the model this would translate to faster decay of persistent firing in conjunctive neurons. It is interesting that patients do not seem to show a decay in precision over time in the incongruent condition. One possibility is that their attention is more likely to switch between items during the delay. Alternatively, decaying persistent firing may weaken feature associations, such that the established synaptic weights are not strong enough to maintain the features of a representation (the features are bound too homogenously). As such, over time the attended representation is less precisely maintained, but the unattended representation is less affected. This may also account for patient misbinding errors in the congruent condition. If the attended item has both faster decay of persistent firing and weaker synaptic weights over time compared with the unattended item, this could lead to more overlap and interference with other features, rendering pattern separation more difficult to achieve and misbinding more likely to occur. A rate-coded model simulating this task has been previously described and demonstrates the need for Hebbian plasticity for both sustained activity and binding (Manohar et al., 2019). To directly simulate the role of NMDARs, the model would need to simulate spiking neurons. Spiking simulations have indeed shown the importance of NMDARs but have not simulated this task specifically (Fiebig et al., 2020). Future simulation work could make more quantitative predictions about how receptor density affects neural activity, memory recall, the effect of delay, and reaction times.

NMDARs are ubiquitous within the brain and this is reflected in the complex neuropsychiatric presentation of the disease, with affective, psychotic, motor and cognitive components. Similarly, WM models require NMDA plasticity in multiple locations and interaction across multiple brain areas. Neural models suggest that NMDAR-related plasticity may be required in both the cortical areas that maintain features (e.g., parietal cortex) and also cortical areas that hold the binding “pointers” (e.g., hippocampus or prefrontal cortex) (Manohar et al., 2019). This makes NMDAR-Ab-E a particularly useful model as it offers a view of specificity in mechanism at the level of cellular computations, even for cognitive functions that, like WM, appear to have little specificity to brain area. This study therefore complements previous work in patients with spatially localized lesions (Aggleton et al., 1986; Pertzov et al., 2013; Yonelinas, 2013; Allen et al., 2014).

The cohort of 10 patients we tested were mostly young women (mean age, 29.2), who had recovered from the acute illness and with good functional outcomes including return to work or full-time education. Some did report residual cognitive difficulty including anxiety, poor sleep, word finding difficulties, and “slowed reading and writing.” Potential confounding factors include the use of psychotropic and anticonvulsant medications. Two patients had been diagnosed with comorbid psychological illnesses which were being treated; two patients reported taking levetiracetam, one sertraline and one benzodiazepine. Medications or untreated symptoms may have interfered with our results and affected performance. Furthermore, some HCs were taking psychotropic medications, two of whom confirmed they were taking antidepressants. Four patients had suffered two clinical episodes of depression, one of whom was diagnosed during an encephalitis relapse. The main limitations of our study are the small sample size and limited diversity of our cohort. This is because NMDAR-E is a rare disease which more commonly occurs in young women though it is a disease of all ages and both sexes. It would therefore be beneficial to replicate the results in a larger and more diverse group of patients. Finally, a few of our patients were not clinically diagnosed with NMDAR-Ab-E until months after symptoms initially started, making the exact time of disease onset difficult to determine. Here, years from diagnosis was based on date of antibody diagnosis where the data was available, and where unavailable, based on patient reported date of diagnosis.

For 7/10 of our patients, serum NMDAR-IgG titers were available [3/7 at diagnosis (1:320, 1:320, 1:160); 4/7 from later timepoints (average of 625 d from diagnosis—1:80 d424; 1:20 d275; 1:40 d1736; 1:500 d74)]. While the presence of current antibodies could theoretically impact function, PET imaging evidence demonstrates that receptor hypofunction continues posttreatment (Galovic et al., 2023) and serum titers do not correlate perfectly with disease course (Gresa-Arribas et al., 2014). Furthermore, the effect we were particularly interested in examining here was not specifically based on the presence of antibodies in these patients but on the NMDA receptor hypofunction induced by the antibodies and the effects of this receptor deficit on WM. Therefore, antibody status/titer or their treatment-related improvements are not directly relevant to our specific objectives.

It should be highlighted this is a disease where treatment largely focuses on acute control with immunomodulation, while longer-term neurological rehabilitation to compensate for NMDAR abnormalities is hugely underexplored. These findings suggest a specific long-term neuropsychological deficit in this patient group which has not previously been reported in any other studies to our knowledge. Our results indicate patients experience WM deficits years postdiagnosis (4.02 mean years since diagnosis) highlighting an important focus for future research. Targeting NMDAR after initial recovery may provide benefit for longer-term neuropsychological sequelae. Agents could include positive allosteric modulators such as D-cycloserine which has previously been trialed with schizophrenia though effects have been poor thus far (Kuppili et al., 2021). Targeting associated proteins such as EphB2 receptors could also prove beneficial. These receptors are known to modulate NMDARs, and evidence has demonstrated that autoantibody-mediated NMDAR loss is prevented by EphB2 receptor activation (Mikasova et al., 2012).

Furthermore, poor attention and WM are important subjective findings but can be difficult to quantify especially in the context of a patient attending a medical clinic. Current clinical tools for assessing NMDAR function are minimal. There may be a clinical utility in this retrocue task, easily completed on a computer, as a neuropsychological assay to help quantify recovery posttreatment in both a clinical setting and outcome studies particularly when assessing symptoms >12 months posttreatment where specific neuropsychological tasks may prove more sensitive (Guasp et al., 2022).