More Is Less: Increased Processing of Unwanted Memories Facilitates Forgetting.

The intention to forget can produce long-lasting effects. This ability has been linked to suppression of both rehearsal and retrieval of unwanted memories, processes mediated by the prefrontal cortex and hippocampus. Here, we describe an alternative account in which the intention to forget is associated with increased engagement with the unwanted information. We used pattern classifiers to decode human functional magnetic resonance imaging data from a task in which male and female participants viewed a series of pictures and were instructed to remember or forget each one. Pictures followed by a forget instruction elicited higher levels of processing in the ventral temporal cortex compared with those followed by a remember instruction. This boost in processing led to more forgetting, particularly for items that showed moderate (vs weak or strong) activation. This result is consistent with the nonmonotonic plasticity hypothesis, which predicts weakening and forgetting of memories that are moderately activated.SIGNIFICANCE STATEMENT The human brain cannot remember everything. Forgetting has a critical role in curating memories and discarding unwanted information. Intentional forgetting has traditionally been linked to passive processes, such as the withdrawal of sustained attention or a stoppage of memory rehearsal. It has also been linked to active suppression of memory processes during encoding and retrieval. Using functional magnetic resonance imaging and machine-learning methods, we show new evidence that intentional forgetting involves an enhancement of memory processing in the sensory cortex to achieve desired forgetting of recent visual experiences. This enhancement temporarily boosts the activation of the memory representation and renders it vulnerable to disruption via homeostatic regulation. Contrary to intuition, deliberate forgetting may involve more rather than less attention to unwanted information.

Cortico-Brainstem Mechanisms of Biased Perceptual Decision-Making in the Context of Pain.

Prior expectations can bias how we perceive pain. Using a drift diffusion model, we recently showed that this influence is primarily based on changes in perceptual decision-making (indexed as shift in starting point). Only during unexpected application of high-intensity noxious stimuli, altered information processing (indexed as increase in drift rate) explained the expectancy effect on pain processing. Here, we employed functional magnetic resonance imaging to investigate the neural basis of both these processes in healthy volunteers. On each trial, visual cues induced the expectation of high- or low-intensity noxious stimulation or signaled equal probability for both intensities. Participants categorized a subsequently applied electrical stimulus as either low- or high-intensity pain. A shift in starting point towards high pain correlated negatively with right dorsolateral prefrontal cortex activity during cue presentation underscoring its proposed role of "keeping pain out of mind". This anticipatory right dorsolateral prefrontal cortex signal increase was positively correlated with periaqueductal gray (PAG) activity when the expected high-intensity stimulation was applied. A drift rate increase during unexpected high-intensity pain was reflected in amygdala engagement and increased functional connectivity between amygdala and PAG. Our findings suggest involvement of the PAG in both decision-making bias and altered information processing to implement expectancy effects on pain. PERSPECTIVE: Modulation of pain through expectations has been linked to changes in perceptual decision-making and altered processing of afferent information. Our results suggest involvement of the dorsolateral prefrontal cortex, amygdala, and periaqueductal gray in these processes.

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.

Occupational attainment influences longitudinal decline in behavioral variant frontotemporal degeneration.

To evaluate whether occupational attainment influences the trajectory of longitudinal cognitive decline in behavioral variant frontotemporal degeneration (bvFTD). Single-center, retrospective, longitudinal study. Sixty-three patients meeting consensus criteria for bvFTD underwent evaluation at the University of Pennsylvania Frontotemporal Degeneration Center. All patients were studied longitudinally on letter-guided fluency, category-naming fluency and Boston Naming Test (BNT). Occupational attainment was defined categorically by assigning each individual's occupation to a professional or non-professional category. Linear mixed-effects models evaluated the interaction of neuropsychological performance change with occupational status. Regression analyses were used to relate longitudinal decline in executive function to baseline MRI grey matter atrophy. Higher occupational status was associated with a more severe slope of cognitive decline on letter-guided fluency and category-naming fluency, but not BNT. Faster rates of longitudinal decline on letter-guided and category-naming fluency were associated with more severe baseline grey matter atrophy in right dorsolateral and inferior frontal regions. Our longitudinal findings suggest that bvFTD individuals with higher lifetime cognitive experience demonstrate more rapid decline on measures of executive function. This finding converges with cross-sectional evidence suggesting that lifetime cognitive experiences contribute to heterogeneity in clinical progression in bvFTD.

UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis.

The majority (90%-95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted magnetic resonance imaging (N = 109) relative to controls (N = 113), and observed that minor allele (C) carriers exhibited greater reduction of cortical thickness in the dorsal prefrontal, ventromedial prefrontal, anterior temporal, and middle temporal cortices and worse performance on a frontal lobe-mediated cognitive test (reverse digit span). In sporadic ALS with autopsy data (N = 102), minor allele homozygotes exhibited greater burden of phosphorylated tar DNA-binding protein-43 kda (TDP-43) pathology in the middle frontal, middle temporal, and motor cortices. Our findings demonstrate converging evidence that rs12608932 may modify frontotemporal disease in sporadic ALS and suggest that rs12608932 may function as a prognostic indicator and could be used to define patient endophenotypes in clinical trials.

Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

Amyotrophic lateral sclerosis (ALS) and the behavioral variant of frontotemporal dementia (bvFTD) commonly share the presence of transactive response DNA-binding protein 43 (TDP-43) inclusions. Structural magnetic resonance imaging studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology-associated brain alterations in TDP-43 proteinopathies. Cortical thickness (CT) and perfusion measurements were obtained in ALS (N = 18), pathologically and/or genetically confirmed bvFTD-TDP (N = 12), and healthy controls (N = 33). bvFTD showed reduced frontotemporal CT, hypoperfusion encompassing orbitofrontal and temporal cortices, and hyperperfusion in motor and occipital regions. ALS did not show reduced CT, but exhibited hypoperfusion in motor and temporal regions, and hyperperfusion in frontal and occipital cortices. Frontotemporal hypoperfusion and reduced CT correlated with cognitive and behavioral impairments as investigated using Mini-Mental State Examination and Philadelphia Brief Assessment of Cognition in bvFTD, and hypoperfusion in motor regions correlated with motor disability as measured by the ALS Functional Rating Scale-Revised in ALS. Hypoperfusion marked early pathologically involved regions, while hyperperfusion characterized regions of late pathological involvement. Distinct perfusion patterns may provide early markers of pathology distribution in TDP-43 proteinopathies.

Cognitive reserve in frontotemporal degeneration: Neuroanatomic and neuropsychological evidence.

OBJECTIVE: To evaluate if cognitive reserve (CR) contributes to interindividual differences in frontal gray matter density (GMD) and executive impairment that underlie heterogeneity in the disease course of confirmed frontotemporal lobar degeneration (FTLD) pathology. METHODS: Fifty-five patients with autopsy confirmation or a pathogenic mutation consistent with underlying tau (FTLD-tau) or TDP-43 (FTLD-TDP) pathology and 90 demographically comparable healthy controls were assessed with T1 MRI and neuropsychological measures (Mini-Mental State Examination, letter fluency, forward digit span, Rey complex figure, and Boston Naming Test). CR was indexed using a composite measure of education and occupation. We used t tests to identify reduced GMD in patients with FTLD relative to controls, regression analyses to relate reduced GMD to CR index, and correlations to relate regions of GMD associated with CR to performance on neuropsychological measures. RESULTS: Patients with FTLD demonstrated impairment on neuropsychological measures. Patients with FTLD exhibited reduced bilateral frontotemporal GMD relative to controls, consistent with the known anatomic distribution of FTLD pathology. Higher CR index was associated with superior letter fluency and with GMD in right dorsolateral prefrontal cortex, orbitofrontal cortex, rostral frontal cortex, and inferior frontal gyrus. Furthermore, we found that higher GMD in frontal regions associated with CR was associated with superior letter fluency. CONCLUSIONS: Executive control and verbal ability assessed by letter fluency in FTLD is mediated in part by CR and frontal GMD. The identification of factors influencing cognitive and anatomic heterogeneity in FTLD suggests that CR should be considered in symptom detection, prognosis, and treatment.

Impairments in set-shifting but not reversal learning in the neonatal ventral hippocampal lesion model of schizophrenia: further evidence for medial prefrontal deficits.

The executive function processes of set-shifting and reversal learning in rodents are mediated by the medial prefrontal cortex and the orbitofrontal cortex, respectively. Here, we investigated both set-shifting and reversal learning in a developmental animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. The NVHL manipulation is known to disrupt development of the medial prefrontal cortex, and to impair behaviors dependent on this area, but potential orbitofrontal abnormalities and reversal learning deficits are less well studied. Animals received excitotoxic lesions of the ventral hippocampus (NVHL) or a sham treatment during the first postnatal week, and all animals were subsequently tested in adulthood on either an operant set-shifting or an operant reversal task. Results indicated that NVHL animals were able to acquire a simple discrimination rule and exhibited normal reversal learning, but were impaired on a prefrontal-dependent set-shifting task. Furthermore, this set-shifting deficit was due to an increase in perseverative errors, which indicate difficulty suppressing a previously learned strategy and result from medial prefrontal insult. Together, these results confirm and extend the idea that cognitive impairments in the NVHL animal are primarily driven by medial prefrontal abnormalities, while the orbitofrontal cortex may remain relatively unaffected.