Locus Coeruleus Integrity Is Linked to Response Inhibition Deficits in Parkinson's Disease and Progressive Supranuclear Palsy.

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of "race models" of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer nondecision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioral modeling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioral changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimization of noradrenergic treatment is likely to benefit from stratification according to LC integrity.SIGNIFICANCE STATEMENT Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson's disease and progressive supranuclear palsy. We used cognitive modeling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson's disease and progressive supranuclear palsy.

Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Noradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes.

Apathy is a debilitating feature of many neuropsychiatric diseases, that is typically described as a reduction of goal-directed behaviour. Despite its prevalence and prognostic importance, the mechanisms underlying apathy remain controversial. Degeneration of the locus coeruleus-noradrenaline system is known to contribute to motivational deficits, including apathy. In healthy people, noradrenaline has been implicated in signalling the uncertainty of expectations about the environment. We proposed that noradrenergic deficits contribute to apathy by modulating the relative weighting of prior beliefs about action outcomes. We tested this hypothesis in the clinical context of Parkinson's disease, given its associations with apathy and noradrenergic dysfunction. Participants with mild-to-moderate Parkinson's disease (N = 17) completed a randomised double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at ultra-high field 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson's disease, subject to stratification according to locus coeruleus integrity. More broadly, these results reconcile emerging predictive processing accounts of the role of noradrenaline in goal-directed behaviour with the clinical symptom of apathy and its potential pharmacological treatment.

Locus Coeruleus Integrity from 7 T MRI Relates to Apathy and Cognition in Parkinsonian Disorders.

BACKGROUND: Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. OBJECTIVES: This study aimed to characterize the spatial patterns of LC pathological change in PD and PSP and the transdiagnostic relationship between LC signals and neuropsychiatric symptoms. METHODS: Twenty-five people with idiopathic PD, 14 people with probable PSP-Richardson's syndrome, and 24 age-matched healthy controls were recruited. Participants underwent clinical assessments and high-resolution (0.08 mm3 ) 7 T-magnetization-transfer imaging to measure LC integrity in vivo. Spatial patterns of LC change were obtained using subregional mean contrast ratios and significant LC clusters; we further correlated the LC contrast with measures of apathy and cognition, using both mixed-effect models and voxelwise analyses. RESULTS: PSP and PD groups showed significant LC degeneration in the caudal subregion relative to controls. Mixed-effect models revealed a significant interaction between disease-group and apathy-related correlations with LC degeneration (ß = 0.46, SE [standard error] = 0.17, F(1, 35) = 7.46, P = 0.01), driven by a strong correlation in PSP (ß = -0.58, SE = 0.21, t(35) = -2.76, P = 0.009). Across both disease groups, voxelwise analyses indicated that lower LC integrity was associated with worse cognition and higher apathy scores. CONCLUSIONS: The relationship between LC and nonmotor symptoms highlights a role for noradrenergic dysfunction across both PD and PSP, confirming the potential for noradrenergic therapeutic strategies to address transdiagnostic cognitive and behavioral features in neurodegenerative disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease.

Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson's disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomized crossover design, 19 patients with Parkinson's disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetization transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in patients with Parkinson's disease. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalized treatment approaches.

An in vivo probabilistic atlas of the human locus coeruleus at ultra-high field.

Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinson's disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent with post mortem findings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structure in vivo at high-resolution (0.4 × 0.4 × 0.5 mm). Magnetisation transfer images from 53 healthy older volunteers (52 - 84 years) clearly revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults. This atlas may be especially relevant for studying disorders associated with older age. To use the atlas does not require use of the same MT sequence of 7T MRI, provided good co-registration and normalisation is achieved. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance along the LC were observed, mirroring distinctive ex vivo spatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset will be made available for non-commercial research, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies.

GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition.

Behavioural disinhibition is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD). It is associated with high morbidity and lacks proven symptomatic treatments. A potential therapeutic strategy is to correct the neurotransmitter deficits associated with FTLD, thereby improving behaviour. Reductions in the neurotransmitters glutamate and GABA correlate with impulsive behaviour in several neuropsychiatric diseases and there is post-mortem evidence of their deficit in FTLD. Here, we tested the hypothesis that prefrontal glutamate and GABA levels are reduced by FTLD in vivo, and that their deficit is associated with impaired response inhibition. Thirty-three participants with a syndrome associated with FTLD (15 patients with behavioural variant frontotemporal dementia and 18 with progressive supranuclear palsy, including both Richardson's syndrome and progressive supranuclear palsy-frontal subtypes) and 20 healthy control subjects were included. Participants undertook ultra-high field (7 T) magnetic resonance spectroscopy and a stop-signal task of response inhibition. We measured glutamate and GABA levels using semi-LASER magnetic resonance spectroscopy in the right inferior frontal gyrus, because of its strong association with response inhibition, and in the primary visual cortex, as a control region. The stop-signal reaction time was calculated using an ex-Gaussian Bayesian model. Participants with frontotemporal dementia and progressive supranuclear palsy had impaired response inhibition, with longer stop-signal reaction times compared with controls. GABA concentration was reduced in patients versus controls in the right inferior frontal gyrus, but not the occipital lobe. There was no group-wise difference in partial volume corrected glutamate concentration between patients and controls. Both GABA and glutamate concentrations in the inferior frontal gyrus correlated inversely with stop-signal reaction time, indicating greater impulsivity in proportion to the loss of each neurotransmitter. We conclude that the glutamatergic and GABAergic deficits in the frontal lobe are potential targets for symptomatic drug treatment of frontotemporal dementia and progressive supranuclear palsy.

Multi-site harmonization of 7 tesla MRI neuroimaging protocols.

Increasing numbers of 7 T (7 T) magnetic resonance imaging (MRI) scanners are in research and clinical use. 7 T MRI can increase the scanning speed, spatial resolution and contrast-to-noise-ratio of many neuroimaging protocols, but technical challenges in implementation have been addressed in a variety of ways across sites. In order to facilitate multi-centre studies and ensure consistency of findings across sites, it is desirable that 7 T MRI sites implement common high-quality neuroimaging protocols that can accommodate different scanner models and software versions. With the installation of several new 7 T MRI scanners in the United Kingdom, the UK7T Network was established with an aim to create a set of harmonized structural and functional neuroimaging sequences and protocols. The Network currently includes five sites, which use three different scanner platforms, provided by two different vendors. Here we describe the harmonization of functional and anatomical imaging protocols across the three different scanner models, detailing the necessary changes to pulse sequences and reconstruction methods. The harmonized sequences are fully described, along with implementation details. Example datasets acquired from the same subject on all Network scanners are made available. Based on these data, an evaluation of the harmonization is provided. In addition, the implementation and validation of a common system calibration process is described.

Multi-centre, multi-vendor reproducibility of 7T QSM and R2* in the human brain: Results from the UK7T study.

INTRODUCTION: We present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network's "Travelling Heads" study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5-3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies. METHODS: Ten healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each "home" site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space. RESULTS AND DISCUSSION: Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001-0.005 ppm (χ) and 0.0005-0.001 ms-1 (R2*). For χ this is 2.1-4.8 fold better than 3T reports, and 1.1-3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol. CONCLUSION: The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.

Improving fMRI in signal drop-out regions at 7 T by using tailored radio-frequency pulses: application to the ventral occipito-temporal cortex.

OBJECTIVE: Signal drop-off occurs in echo-planar imaging in inferior brain areas due to field gradients from susceptibility differences between air and tissue. Tailored-RF pulses based on a hyperbolic secant (HS) have been shown to partially recover signal at 3 T, but have not been tested at higher fields. MATERIALS AND METHODS: The aim of this study was to compare the performance of an optimized tailored-RF gradient-echo echo-planar imaging (TRF GRE-EPI) sequence with standard GRE-EPI at 7 T, in a passive viewing of faces or objects fMRI paradigm in healthy subjects. RESULTS: Increased temporal-SNR (tSNR) was observed in the middle and inferior temporal lobes and orbitofrontal cortex of all subjects scanned, but elsewhere tSNR decreased relative to the standard acquisition. In the TRF GRE-EPI, increased functional signal was observed in the fusiform, lateral occipital cortex, and occipital pole, regions known to be part of the visual pathway involved in face-object perception. CONCLUSION: This work highlights the potential of TRF approaches at 7 T. Paired with a reversed-gradient distortion correction to compensate for in-plane susceptibility gradients, it provides an improved acquisition strategy for future neurocognitive studies at ultra-high field imaging in areas suffering from static magnetic field inhomogeneities.

Assessment of Silent T1-weighted head imaging at 7 T.

OBJECTIVES: This study aimed to assess the performance of a "Silent" zero time of echo (ZTE) sequence for T1-weighted brain imaging using a 7 T MRI system. METHODS: The Silent sequence was evaluated qualitatively by two neuroradiologists, as well as quantitatively in terms of tissue contrast, homogeneity, signal-to-noise ratio (SNR) and acoustic noise. It was compared to conventional T1-weighted imaging (FSPGR). Adequacy for automated segmentation was evaluated in comparison with FSPGR acquired at 7 T and 1.5 T. Specific absorption rate (SAR) was also measured. RESULTS: Tissue contrast and homogeneity in Silent were remarkable in deep brain structures and in the occipital and temporal lobes. Mean tissue contrast was significantly (p < 0.002) higher in Silent (0.25) than in FSPGR (0.11), which favoured automated tissue segmentation. On the other hand, Silent images had lower SNR with respect to conventional imaging: average SNR of FSPGR was 2.66 times that of Silent. Silent images were affected by artefacts related to projection reconstruction, which nevertheless did not compromise the depiction of brain tissues. Silent acquisition was 35 dB(A) quieter than FSPGR and less than 2.5 dB(A) louder than ambient noise. Six-minute average SAR was <2 W/kg. CONCLUSIONS: The ZTE Silent sequence provides high-contrast T1-weighted imaging with low acoustic noise at 7 T. KEY POINTS: • "Silent" is an MRI technique allowing zero time of echo acquisition • Its feasibility and performance were assessed on a 7 T MRI system • Image quality in several regions was higher than in conventional techniques • Imaging acoustic noise was dramatically reduced compared with conventional imaging • "Silent" is suitable for T1-weighted head imaging at 7 T.

Differential tangential expansion as a mechanism for cortical gyrification.

Gyrification, the developmental buckling of the cortex, is not a random process-the forces that mediate expansion do so in such a way as to generate consistent patterns of folds across individuals and even species. Although the origin of these forces is unknown, some theories have suggested that they may be related to external cortical factors such as axonal tension. Here, we investigate an alternative hypothesis, namely, whether the differential tangential expansion of the cortex alone can account for the degree and pattern-specificity of gyrification. Using intrinsic curvature as a measure of differential expansion, we initially explored whether this parameter and the local gyrification index (used to quantify the degree of gyrification) varied in a regional-specific pattern across the cortical surface in a manner that was replicable across independent datasets of neurotypicals. Having confirmed this consistency, we further demonstrated that within each dataset, the degree of intrinsic curvature of the cortex was predictive of the degree of cortical folding at a global and regional level. We conclude that differential expansion is a plausible primary mechanism for gyrification, and propose that this perspective offers a compelling mechanistic account of the co-localization of cytoarchitecture and cortical folds.

Structural neuroimaging correlates of allelic variation of the BDNF val66met polymorphism.

BACKGROUND: The brain-derived neurotrophic factor (BDNF) val66met polymorphism is associated with altered activity dependent secretion of BDNF and a variable influence on brain morphology and cognition. Although a met-dose effect is generally assumed, to date the paucity of met-homozygotes have limited our understanding of the role of the met-allele on brain structure. METHODS: To investigate this phenomenon, we recruited sixty normal healthy subjects, twenty in each genotypic group (val/val, val/met and met/met). Global and local morphology were assessed using voxel based morphometry and surface reconstruction methods. White matter organisation was also investigated using tract-based spatial statistics and constrained spherical deconvolution tractography. RESULTS: Morphological analysis revealed an "inverted-U" shaped profile of cortical changes, with val/met heterozygotes most different relative to the two homozygous groups. These results were evident at a global and local level as well as in tractography analysis of white matter fibre bundles. CONCLUSION: In contrast to our expectations, we found no evidence of a linear met-dose effect on brain structure, rather our results support the view that the heterozygotic BDNF val66met genotype is associated with cortical morphology that is more distinct from the BDNF val66met homozygotes. These results may prove significant in furthering our understanding of the role of the BDNF met-allele in disorders such as Alzheimer's disease and depression.

7T MRI detects widespread brain iron deposition in neuroferritinopathy.

Neuroferritinopathy is a disorder of neurodegeneration with brain iron accumulation that has no proven disease-modifying treatments. Clinical trials require biomarkers of iron deposition. We examined brain iron accumulation in one presymptomatic FTL mutation carrier, two individuals with neuroferritinopathy and one healthy control using ultra-high-field 7T MRI. There was increased magnetic susceptibility, suggestive of iron deposition, in superficial and deep gray matter in both presymptomatic and symptomatic neuroferritinopathy. Cavitation of the putamen and globus pallidus increased with disease stage and at follow up. The widespread brain iron deposition in presymptomatic and early disease provides an opportunity for monitoring disease-modifying intervention.

Unveiling Lung Adenocarcinoma: Non-bacterial Thrombotic Endocarditis as the Debut Sign.

Non-bacterial thrombotic endocarditis (NBTE) involves the deposition of fibrin and platelets on heart valves, frequently leading to systemic embolism. The association between NBTE and cancer demands thorough investigation in cases lacking an evident cause. This case report elucidates the clinical course of a nonsmoking woman in her sixties with NBTE linked to pulmonary adenocarcinoma. The patient, who had a history of multiple sclerosis (MS) and was receiving dimethyl fumarate treatment, presented to the emergency department with stroke-like symptoms. Diagnostic challenges arose due to preexisting motor sensory impairment from MS. Initial evaluations revealed hypocapnia and elevated inflammatory markers. Blood cultures were obtained twice, and imaging confirmed pneumonia, left pleural effusion, and chronic pulmonary embolism while excluding acute vascular events or intracranial hemorrhage. The first transthoracic echocardiogram (TTE) indicated no cardiac abnormalities. Treatment encompassed parenteral antibiotics, systemic anticoagulation, and admission to medical floors. Although the initial treatment yielded a positive clinical response, subsequent complications emerged. On the tenth day, the patient required additional interventions, including broad-spectrum antibiotics and supplemental oxygen. A follow-up chest X-ray revealed persistent pneumonia and pleural effusion, and blood cultures upon admission returned negative. A subsequent head MRI confirmed an embolic stroke and displayed evidence of MS progression. Around the twentieth day, empirical treatment for infective endocarditis was initiated, and an 8 mm vegetation on the aortic valve was identified via transesophageal echocardiography (TOE). Acute pulmonary edema prompted a transfer to the intermediate care unit. Further investigations, including left thoracocentesis and CT, unveiled exudate and metastatic lesions in the liver, ilium, and kidney. Unfortunately, on the twenty-fifth day, the patient experienced acute myocardial infarction, right leg ischemia, disseminated intravascular coagulation, and shock. Pleural fluid analysis revealed malignant cells suggestive of lung adenocarcinoma. This case underscores the pivotal role of timely NBTE recognition and the search for malignancy when workup for infective endocarditis and autoimmune panels is negative. Moreover, it emphasizes the significance of vigilant monitoring, particularly in immunocompromised individuals or those with preexisting neurological deficits, especially when new neurological symptoms manifest. These insights significantly contribute to the comprehension of NBTE management and its implications for analogous patient cohorts.

Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls.

There has been little analysis of neurochemical correlates of compulsive behaviour to illuminate its underlying neural mechanisms. We use 7-Tesla proton magnetic resonance spectroscopy (1H-MRS) to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex (ACC) and supplementary motor area (SMA) of healthy volunteers and participants with Obsessive-Compulsive Disorder (OCD). Within the SMA, trait and clinical measures of compulsive behaviour are related to glutamate levels, whereas a behavioural index of habitual control correlates with the glutamate:GABA ratio. Participants with OCD also show the latter relationship in the ACC while exhibiting elevated glutamate and lower GABA levels in that region. This study highlights SMA mechanisms of habitual control relevant to compulsive behaviour, common to the healthy sub-clinical and OCD populations. The results also demonstrate additional involvement of anterior cingulate in the balance between goal-directed and habitual responding in OCD.

Path integration selectively predicts midlife risk of Alzheimer's disease.

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

Temporal lobe perceptual predictions for speech are instantiated in motor cortex and reconciled by inferior frontal cortex.

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phonological information and weighted prediction error. In the presence of intact temporal cortex, frontal neurodegeneration results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predictions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech.

Parallel transmit (pTx) with online pulse design for task-based fMRI at 7 T.

PURPOSE: Parallel transmission (pTx) is an approach to improve image uniformity for ultra-high field imaging. In this study, we modified an echo planar imaging (EPI) sequence to design subject-specific pTx pulses online. We compared its performance against EPI with conventional circularly polarised (CP) pulses. METHODS: We compared the pTx-EPI and CP-EPI sequences in a short EPI acquisition protocol and for two different functional paradigms in six healthy volunteers (2 female, aged 23-36 years, mean age 29.2 years). We chose two paradigms that are typically affected by signal dropout at 7 T: a visual objects localiser to determine face/scene selective brain regions and a semantic-processing task. RESULTS: Across all subjects, pTx-EPI improved whole-brain mean temporal signal-to-noise ratio (tSNR) by 11.0% compared to CP-EPI. We also compared the ability of pTx-EPI and CP-EPI to detect functional activation for three contrasts over the two paradigms: face > object and scene > object for the visual objects localiser and semantic association > pattern matching for the semantic-processing paradigm. Across all three contrasts, pTx-EPI showed higher median z-scores and detected more active voxels in relevant areas, as determined from previous 3 T studies. CONCLUSION: We have demonstrated a workflow for EPI acquisitions with online per-subject pulse calculations. We saw improved performance in both tSNR and functional acquisitions from pTx-EPI. Thus, we believe that online calculation pTx-EPI is robust enough for future fMRI studies, especially where activation is expected in brain areas liable to significant signal dropout.