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McLaughlin, N.

Publications and source records attributed to McLaughlin, N..

2 recordsLinked to original sources

Cognitive sequences in obsessive-compulsive disorder are supported by frontal cortex ramping activity and mediated by symptom severity

Completing sequences is a routine part of daily life. Many are abstract, defined by a rule governing the order rather than the identity of individual steps (e.g., getting dressed). In obsessive-compulsive disorder (OCD), excessive ritualistic behaviors suggest a disruption in abstract sequence completion. Executing abstract sequences requires at least two levels in a hierarchy of cognitive control: abstract sequential control (tracking steps) and task switching (shifting between tasks). While task switching has been studied in OCD, little is known in a sequential context. Understanding both hierarchical control types is key to uncovering how abstract sequences with nested task switches are processed in OCD. Previous studies showed that the rostrolateral prefrontal cortex (RLPFC) supports abstract sequence monitoring in healthy individuals with an increase in activity across each sequence, a dynamic known as "ramping". Ramping outside the RLPFC is potentially indicative of other sequence-related processes such as progress towards a goal and increasing working memory load. Therefore, we hypothesized that abstract sequential control deficits would correspond to altered ramping dynamics in RLPFC and other cortical regions. Second, we predicted task switching deficits in OCD, coupled with altered activity in cortical regions canonically implicated in task level control. We found partial support for both hypotheses. Abstract sequential control did not show behavioral differences in OCD but did show increased overall ramping in the anterior cingulate cortex (ACC) and superior frontal sulcus (SFS) and ramping differences in additional, novel cortical regions according to abstract sequence complexity. In contrast, behavioral differences were observed for task switching in OCD without neural differences between the groups. Together, these results suggest a group of areas support sequential control differentially in OCD than in healthy controls, despite behavioral similarity, and that this observation is likely not the result of neural deficits in task switching. These findings thus provide insight into OCD during complex behaviors more similar to daily life where sequence and task level control are intertwined and may inform future potential treatment.

neuroscience↗

Absence seizures and sleep abnormalities in a rat model of GRIN2B neurodevelopmental disorder

Pathogenic mutations in GRIN2B are an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism and intellectual disability. GRIN2B encodes the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novel Grin2b heterozygous knockout rat model with 24-hour EEG recordings. We found rats heterozygous for the deletion (Grin2b+/-) had a higher incidence of spontaneous spike and wave discharges, the electrographic correlate of absence seizures, than wild-type rats (Grin2b+/+). Spike and wave discharges were longer in duration and displayed higher overall spectral power in Grin2b+/- when compared to those in Grin2b+/+ animals. Heterozygous mutant rats also had abnormal sleep-wake brain state dynamics over the circadian cycle. Specifically, we identified a reduction in total rapid eye movement sleep and, altered distributions of non-rapid eye movement sleep and wake epochs, when compared to controls. This was accompanied by an increase in overall spectral power during non-rapid eye movement sleep in Grin2b+/-. The sleep-wake phenotypes were largely uncorrelated to the incidence of spike and wave discharges. We then tested the antiseizure efficacy of ethosuximide, a T-type voltage-gated calcium channel blocker used in the treatment of absence seizures, and memantine, a noncompetitive NMDAR antagonist currently explored as a mono or adjunctive treatment option in NMDAR related neurodevelopmental disorders. Ethosuximide reduced the number and duration of spike and wave discharges, while memantine did not affect the number of spike and wave discharges but reduced their duration. These results highlight two potential therapeutic options for GRIN2B related epilepsy. Our data shows the new rat Grin2b haploinsufficiency model exhibits clinically relevant phenotypes. As such, it could prove crucial in deciphering underlying pathological mechanisms and developing new therapeutically translatable strategies for GRIN2B neurodevelopmental disorders.

neuroscience↗