James B. Rowe

Active maintenance in prefrontal area 46 creates distractor-resistant memory

How does the brain maintain information in working memory while challenged by incoming distractions? Using functional magnetic resonance imaging (fMRI), we measured human brain activity during the memory delay of a spatial working memory task with distraction. We found that, in the prefrontal cortex (PFC), the magnitude of activity sustained throughout the memory delay was significantly higher on correct trials than it was on error trials. By contrast, the magnitude of sustained activity in posterior areas did not differ between correct and error trials. The correlation of activity between posterior areas was, however, associated with correct memory performance after distraction. On the basis of these findings, we propose that memory representations gain resistance against distraction during a period of active maintenance within working memory. This may be mediated by interactions between prefrontal and posterior areas.

Feeling the Beat: Premotor and Striatal Interactions in Musicians and Nonmusicians during Beat Perception

Little is known about the underlying neurobiology of rhythm and beat perception, despite its universal cultural importance. Here we used functional magnetic resonance imaging to study rhythm perception in musicians and nonmusicians. Three conditions varied in the degree to which external reinforcement versus internal generation of the beat was required. The “volume” condition strongly externally marked the beat with volume changes, the “duration” condition marked the beat with weaker accents arising from duration changes, and the “unaccented” condition required the beat to be entirely internally generated. In all conditions, beat rhythms compared with nonbeat control rhythms revealed putamen activity. The presence of a beat was also associated with greater connectivity between the putamen and the supplementary motor area (SMA), the premotor cortex (PMC), and auditory cortex. In contrast, the type of accent within the beat conditions modulated the coupling between premotor and auditory cortex, with greater modulation for musicians than nonmusicians. Importantly, the response of the putamen to beat conditions was not attributable to differences in temporal complexity between the three rhythm conditions. We propose that a cortico-subcortical network including the putamen, SMA, and PMC is engaged for the analysis of temporal sequences and prediction or generation of putative beats, especially under conditions that may require internal generation of the beat. The importance of this system for auditory–motor interaction and development of precisely timed movement is suggested here by its facilitation in musicians.

Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent Than Expected in the UK Population

Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.

Working memory for location and time: activity in prefrontal area 46 relates to selection rather than maintenance in memory.

The role of the dorsal prefrontal cortex in working memory remains controversial. Influential proposals include a role in the maintenance of domain-specific information, and the processes of executive functions on remembered information. We used event-related functional magnetic resonance imaging to demonstrate a functional dissociation within prefrontal cortex in terms of the components of complex working memory tasks. The maintenance in working memory of spatial locations and their temporal order was associated with activation of area 8 and intraparietal cortex. In contrast, the selection of one location, according to its order, was associated with a distinct frontoparietal network, including dorsolateral prefrontal area 46, ventrolateral prefrontal cortex and anterior cingulate cortex and medial parietal cortex. The different contributions of these areas to selection are considered in the light of recent electrophysiological and lesion studies. We suggest a general role of the dorsolateral prefrontal area 46 in attentional selection, including selection from within working memory.

Attention to Action: Specific Modulation of Corticocortical Interactions in Humans

The prefrontal cortex may exert cognitive control by a general mechanism of attentional selection of neuronal representations. We used functional magnetic resonance imaging to test this hypothesis in the motor system. Normal volunteers were scanned during performance of a simple motor task, with their attention either directed towards their actions, or diverted towards a visual search task, or neither. Attention to action increased activity in prefrontal, premotor and parietal cortex, compared with unattended performance of the same movements. Analysis of cortical activity by structural equation modelling of regional fMRI time series was used to measure effective connectivity among prefrontal, premotor and parietal cortices. Attention to action enhanced effective connectivity between dorsal prefrontal cortex and premotor cortex, whereas non-motor attention diminished it. These effects were not attributable to common inputs from parietal cortex to the prefrontal and premotor cortex. The results suggest a supra-modal role for the dorsal prefrontal cortex in attentional selection, operating within the motor system as well as sensory and mnemonic domains.

Motion or activity: their role in intra- and inter-subject variation in fMRI.

Functional MRI (fMRI) carries the potential for non-invasive measurements of brain activity. Typically, what are referred to as activation images are actually thresholded statistical parametric maps. These maps possess large inter-session variability. This is especially problematic when applying fMRI to pre-surgical planning because of a higher requirement for intra-subject precision. The purpose of this study was to investigate the impact of residual movement artefacts on intra-subject and inter-subject variability in the observed fMRI activation. Ten subjects were examined using three different word-generation tasks. Two of the subjects were examined 10 times on 10 different days using the same paradigms. We systematically investigated one approach of correcting for residual movement effects: the inclusion of regressors describing movement-related effects in the design matrix of a General Linear Model (GLM). The data were analysed with and without modeling the residual movement artefacts and the impact on inter-session variance was assessed using F-contrasts. Inclusion of motion parameters in the analysis significantly reduced both the intra-subject as well as the inter-subject-variance.

Characterizing mild cognitive impairment in incident Parkinson disease: The ICICLE-PD Study

Objective: To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers. Methods: Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria. Results: The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1–42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1–42 and 1–40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold. Conclusions: In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1–42 and 1–40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

Motor Imagery After Stroke: Relating Outcome to Motor Network Connectivity

Neuroplasticity is essential for recovery after stroke and is the target for new stroke therapies. During recovery from subcortical motor stroke, brain activations associated with movement may appear normal despite residual functional impairment. This raises an important question: how far does recovery of motor performance depend on the processes that precede movement execution involving the premotor and prefrontal cortex, rather than recovery of the corticospinal system alone?

Neural activity associated with monitoring the oscillating threat value of a tarantula

Phylogenetic threats such as spiders evoke our deepest primitive fears. When close or looming, such threats engage evolutionarily conserved monitoring systems and defense reactions that promote self-preservation. With the use of a modified behavioral approach task within functional MRI, we show that, as a tarantula was placed closer to a subjects foot, increased experiences of fear coincided with augmented activity in a cascade of fear-related brain networks including the periaqueductal gray, amygdala, and bed nucleus of the stria terminalis. Activity in the amygdala was also associated with underprediction of the tarantulas threat value and, in addition to the bed nucleus of the stria terminalis, with monitoring the tarantulas threat value as indexed by its direction of movement. Conversely, the orbitofrontal cortex was engaged as the tarantula grew more distant, suggesting that this region emits safety signals or expels fear. Our findings fractionate the neurobiological mechanisms associated with basic fear and potentially illuminate the perturbed reactions that characterize clinical phobias.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

BACKGROUND Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING Centres of Excellence in Neurodegeneration.