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Background: Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson's disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer's disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance. Methods: Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity. Results: Episodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes. Conclusions: This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD. Trial registration: ClinicalTrials.gov, NCT04643327. Registered on 25 November 2020. [ABSTRACT FROM AUTHOR]

Comprehending action words often engages similar brain regions to those involved in perceiving and executing actions. This finding has been interpreted as support for grounding of conceptual processing in motor representations or that conceptual processing involves motor simulation. However, such demonstrations cannot confirm the nature of the mechanism(s) responsible, as word comprehension involves multiple processes (e.g., lexical, semantic, morphological, phonological). In this study, we tested whether this motor cortex engagement instead reflects processing of statistical regularities in sublexical phonological features. Specifically, we measured brain activity in healthy participants using functional magnetic resonance imaging while they performed an auditory lexical decision paradigm involving monosyllabic action words associated with specific effectors (face, arm, and leg). We show that nonwords matched to the action words in terms of their phonotactic probability elicit common patterns of activation. In addition, we show that a measure of the action words' phonological typicality, the extent to which a word's phonology is typical of other words in the grammatical category to which it belongs (i.e., more or less verb-like), is responsible for their activating a significant portion of primary and premotor cortices. These results indicate motor cortex engagement during action word comprehension is more likely to reflect processing of statistical regularities in sublexical phonological features than conceptual processing. We discuss the implications for current neurobiological models of language, all of which implicitly or explicitly assume that the relationship between the sound of a word and its meaning is arbitrary. [ABSTRACT FROM AUTHOR]

Aim: Frontal and posterior‐cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior‐cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting‐state functional magnetic resonance imaging (rs‐fMRI). Methods: K‐means cluster analysis delineated subtypes (cognitively intact, frontal, posterior‐cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N = 42) and 20 healthy controls (HCs) underwent rs‐fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior‐cortical, cognitively intact, and HC participants using seed‐based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. Results: The posterior‐cortical subtype (N = 19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N = 11) group, p‐false discovery rate (FDR) =.01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N = 20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p‐FDR =.01). Conclusion: Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior‐cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted. [ABSTRACT FROM AUTHOR]

• Few studies have investigated fMRI language paradigm validity at an individual level. • Regions beyond the core language network should be considered for neurosurgical use. • Tasks differ in suitability for use as clinical biomarkers of language outcome. Most functional MRI studies of language processing have focussed on group-level inference, but for clinical use, the aim is to predict outcomes at an individual patient level. This requires being able to identify atypical activation and understand how differences relate to language outcomes. A language mapping paradigm that selectively activates left hemisphere language regions in healthy individuals allows atypical activation in a patient to be more easily identified. We investigated the interindividual variability and consistency of language activation in 12 healthy participants using three tasks—verb generation, responsive naming, and sentence comprehension—for future presurgical use. Responsive naming produced the most consistent left-lateralised activation across participants in frontal and temporal regions that postsurgical voxel-based lesion-symptom mapping studies suggest are most critical for language outcomes. Studies with a long-term clinical aim of predicting language outcomes in neurosurgical patients and stroke patients should first establish paradigm validity at an individual level in healthy participants. [ABSTRACT FROM AUTHOR]

Studies of context effects in speech production have shown that semantic feature overlap produces interference in naming of categorically related objects. In neuroimaging studies, this semantic interference effect is consistently associated with involvement of left superior and middle temporal gyri. However, at least part of this effect has recently been shown to be attributable to visual form similarity, as categorically related objects typically share visual features. This fMRI study examined interference produced by visual form overlap in the absence of a category relation in a picture–word interference paradigm. Both visually similar and visually dissimilar distractors led to increased BOLD responses in the left inferior frontal gyrus compared with the congruent condition. Naming pictures in context with a distractor word denoting an object visually similar in form slowed RTs compared with unrelated words and was associated with reduced activity in the left posterior middle temporal gyrus. This area is reliably observed in lexical level processing during language production tasks. No significant differential activity was observed in areas typically engaged by early perceptual or conceptual feature level processing or in areas proposed to be engaged by postlexical language processes, suggesting that visual form interference does not arise from uncertainty or confusion during perceptual or conceptual identification or after lexical processing. We conclude that visual form interference has a lexical locus, consistent with the predictions of competitive lexical selection models. [ABSTRACT FROM AUTHOR]

Every language has words deemed to be socially inappropriate or 'taboo' to utter. Taboo word production appears prominently in language disorders following brain injury. Yet, we know little about the cognitive and neural mechanisms involved in processing taboo compared to neutral language. In the present study, we introduced taboo distractor words in the picture word interference paradigm during functional magnetic resonance imaging to investigate how these words influence spoken word production. Taboo distractor words significantly slowed picture-naming latencies compared to neutral words. This interference effect was associated with increased blood oxygen level dependent signal across a distributed thalamo-cortical network including bilateral anterior cingulate cortex and left inferior frontal gyrus, left posterior middle temporal gyrus and right thalamus. We interpret our findings as being consistent with an account integrating both domain-general attention-capture/distractor blocking and language-specific mechanisms in processing taboo words during spoken word production. [ABSTRACT FROM AUTHOR]

Head motion (HM) is a well known confound in analyses of functional MRI (fMRI) data. Neuroimaging researchers therefore typically treat HM as a nuisance covariate in their analyses. Even so, it is possible that HM shares a common genetic influence with the trait of interest. Here we investigate the extent to which this relationship is due to shared genetic factors, using HM extracted from resting-state fMRI and maternal and self report measures of Inattention and Hyperactivity-Impulsivity from the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) scales. Our sample consisted of healthy young adult twins (N = 627 (63% females) including 95 MZ and 144 DZ twin pairs, mean age 22, who had mother-reported SWAN; N = 725 (58% females) including 101 MZ and 156 DZ pairs, mean age 25, with self reported SWAN). This design enabled us to distinguish genetic from environmental factors in the association between head movement and ADHD scales. HM was moderately correlated with maternal reports of Inattention (r = 0.17, p-value = 7.4E-5) and Hyperactivity-Impulsivity (r = 0.16, p-value = 2.9E-4), and these associations were mainly due to pleiotropic genetic factors with genetic correlations [95% CIs] of rg = 0.24 [0.02, 0.43] and rg = 0.23 [0.07, 0.39]. Correlations between self-reports and HM were not significant, due largely to increased measurement error. These results indicate that treating HM as a nuisance covariate in neuroimaging studies of ADHD will likely reduce power to detect between-group effects, as the implicit assumption of independence between HM and Inattention or Hyperactivity-Impulsivity is not warranted. The implications of this finding are problematic for fMRI studies of ADHD, as failing to apply HM correction is known to increase the likelihood of false positives. We discuss two ways to circumvent this problem: censoring the motion contaminated frames of the RS-fMRI scan or explicitly modeling the relationship between HM and Inattention or Hyperactivity-Impulsivity. [ABSTRACT FROM AUTHOR]

The hemodynamic response function (HRF) describes the local response of brain vasculature to functional activation. Accurate HRF modeling enables the investigation of cerebral blood flow regulation and improves our ability to interpret fMRI results. Block designs have been used extensively as fMRI paradigms because detection power is maximized; however, block designs are not optimal for HRF parameter estimation. Here we assessed the utility of block design fMRI data for HRF modeling. The trueness (relative deviation), precision (relative uncertainty), and identifiability (goodness-of-fit) of different HRF models were examined and test-retest reproducibility of HRF parameter estimates was assessed using computer simulations and fMRI data from 82 healthy young adult twins acquired on two occasions 3 to 4 months apart. The effects of systematically varying attributes of the block design paradigm were also examined. In our comparison of five HRF models, the model comprising the sum of two gamma functions with six free parameters had greatest parameter accuracy and identifiability. Hemodynamic response function height and time to peak were highly reproducible between studies and width was moderately reproducible but the reproducibility of onset time was low. This study established the feasibility and test-retest reliability of estimating HRF parameters using data from block design fMRI studies. [ABSTRACT FROM AUTHOR]

Abstract: Prior phonological processing can enhance subsequent picture naming performance in individuals with aphasia, yet the neurocognitive mechanisms underlying this effect and its longevity are unknown. This study used functional magnetic resonance imaging to examine the short-term (within minutes) and long-term (within days) facilitation effects from a phonological task in both participants with aphasia and age-matched controls. Results for control participants suggested that long-term facilitation of subsequent picture naming may be driven by a strengthening of semantic–phonological connections, while semantic and object recognition mechanisms underlie more short-term effects. All participants with aphasia significantly improved in naming accuracy following both short- and long-term facilitation. A descriptive comparison of the neuroimaging results identified different patterns of activation for each individual with aphasia. The exclusive engagement of a left hemisphere phonological network underlying facilitation was not revealed. The findings suggest that improved naming in aphasia with phonological tasks may be supported by changes in right hemisphere activity in some individuals and reveal the potential contribution of the cerebellum to improved naming following phonological facilitation. Conclusions must be interpreted with caution, however, due to the comparison of corrected group control results to that of individual participants with aphasia, which were not corrected for multiple comparisons. [Copyright &y& Elsevier]

Introduction: Deficits in attentional processing observed in Parkinson's disease (PD) patients with mild cognitive impairment (MCI) increase risk of PD dementia. However, the neural basis of these attentional deficits are presently unknown. The present study aimed to explore the neural correlates of attention dysfunction in PD-MCI using the Attention Network Test (ANT) and functional Magnetic Resonance Imaging (fMRI).Method: Fifteen (15) PD-MCI patients, 26 PD patients without MCI (PD-NC) and 22 healthy controls (HC) were scanned (3T Siemens PRISMA) whilst performing the ANT. Reaction time, accuracy and fMRI BOLD activation were compared between groups for the three attentional task components of 1) alerting, 2) orienting, and 3) executive control.Results: PD-MCI patients showed an overall slower reaction time compared to PD-NC and HC, and showed less interference of reaction time in the orienting effect than HC. fMRI data demonstrated greater activation in the bilateral cerebellum crus 1 during the alerting attention condition in both PD-MCI and PD-NC compared to HC. However, activation was supressed in the left postcentral gyrus in PD-MCI compared to PD-NC and HC.Discussion: Alterations in the alerting attention functional network despite intact task performance in PD-MCI suggests that functional brain changes may precede cognitive changes in the attention domain. Furthermore, increased activation in the cerebellum may reflect an attentional compensatory mechanism unique to the PD pathology. Taken together, the findings suggest that PD has a complex effect on attentional ability that can, at least in part, be elucidated using functional neuroimaging. [ABSTRACT FROM AUTHOR]

Left-hemisphere intraparenchymal primary brain tumor patients are at risk of developing reading difficulties that may be stable, improve or deteriorate after surgery. Previous studies examining language organization in brain tumor patients have provided insights into neural plasticity supporting recovery. Only a single study, however, has examined the role of white matter tracts in preserving reading ability post-surgery and none have examined the functional reading network. The current study aimed to investigate the regional spontaneous brain activity associated with reading performance in a group of 36 adult patients 6–24 months following left-hemisphere tumor resection. Spontaneous brain activity was assessed using resting-state fMRI (rs-fMRI) regional homogeneity (ReHo) and fractional amplitude low frequency fluctuation (fALFF) metrics, which measure local functional connectivity and activity, respectively. ReHo in the left occipito-temporal and right superior parietal regions was negatively correlated with reading performance. fALFF in the putamen bilaterally and the left cerebellum was negatively correlated with reading performance, and positively correlated in the right superior parietal gyrus. These findings are broadly consistent with reading networks reported in healthy participants, indicating that reading ability following brain tumor surgery might not involve substantial functional re-organization. • Left-hemisphere brain tumors place patients at risk for reading difficulties. • The mechanisms of reading performance post-surgery are not well understood. • We examined the functional reading network following brain-tumor surgery. • The reading network for patients post-surgery was similar to that of healthy adults. • Reading ability post-brain tumor surgery may not involve substantial reorganization. [ABSTRACT FROM AUTHOR]

In functional magnetic resonance imaging (fMRI), the hemodynamic response function (HRF) reflects regulation of regional cerebral blood flow in response to neuronal activation. The HRF varies significantly between individuals. This study investigated the genetic contribution to individual variation in HRF using fMRI data from 125 monozygotic (MZ) and 149 dizygotic (DZ) twin pairs. The resemblance in amplitude, latency, and duration of the HRF in six regions in the frontal and parietal lobes was compared between MZ and DZ twin pairs. Heritability was estimated using an ACE (Additive genetic, Common environmental, and unique Environmental factors) model. The genetic influence on the temporal profile and amplitude of HRF was moderate to strong (24%–51%). The HRF may be used in the genetic analysis of diseases with a cerebrovascular etiology. [ABSTRACT FROM AUTHOR]

Head motion (HM) is a critical confounding factor in functional MRI. Here we investigate whether HM during resting state functional MRI (RS-fMRI) is influenced by genetic factors in a sample of 462 twins (65% female; 101 MZ (monozygotic) and 130 DZ (dizygotic) twin pairs; mean age: 21 (SD = 3.16), range 16–29). Heritability estimates for three HM components—mean translation (MT), maximum translation (MAXT) and mean rotation (MR)—ranged from 37 to 51%. We detected a significant common genetic influence on HM variability, with about two-thirds (genetic correlations range 0.76–1.00) of the variance shared between MR, MT and MAXT. A composite metric (HM-PC1), which aggregated these three, was also moderately heritable (h 2 = 42%). Using a sub-sample (N = 35) of the twins we confirmed that mean and maximum translational and rotational motions were consistent “traits” over repeated scans (r = 0.53–0.59); reliability was even higher for the composite metric (r = 0.66). In addition, phenotypic and cross-trait cross-twin correlations between HM and resting state functional connectivities (RS-FCs) with Brodmann areas (BA) 44 and 45, in which RS-FCs were found to be moderately heritable (BA44: h 2 ¯ = 0.23 (sd = 0.041), BA45: h 2 ¯ = 0.26 (sd = 0.061)), indicated that HM might not represent a major bias in genetic studies using FCs. Even so, the HM effect on FC was not completely eliminated after regression. HM may be a valuable endophenotype whose relationship with brain disorders remains to be elucidated. [ABSTRACT FROM AUTHOR]