Matthew A. Lambon Ralph’s research while affiliated with MRC Cognition and Brain Sciences Unit and other places

Control processes underpinned by the prefrontal cortex are critical for generating task-appropriate behaviour across cognitive domains, yet this region develops extremely late. Traditionally, this developmental pattern is considered negative but necessary. However, an alternative (yet perhaps complementary) view suggests that a developmental period without control could support learning, particularly in the semantic domain. Here, we exploit a recent computational model to test formally whether late development of the context-sensitive use of conceptual knowledge, or ‘semantic control’, would promote concept acquisition. Simulations show that late maturation of semantic control and anatomical connectivity conspire to promote conceptual learning. Delayed control speeds conceptual learning without compromising conceptual representations, particularly when control connects to intermediate layers. To assess whether semantic control also develops late in human children, we conducted a meta-analysis of the classic triadic matching task where participants decide which of two options best matches a third. Matching can be based on taxonomic or thematic relations. When these conflict, participants must exert semantic control to determine which relation is task appropriate. Context-sensitivity develops later than conceptual knowledge with large increases between 3 and 6 years. Thus, the protracted PFC development leads to a delay in acquiring semantic control processes, benefiting conceptual learning.

The temporal signal-to-noise ratio (tSNR) of functional magnetic resonance imaging (fMRI) is particularly poor in ventral anterior temporal and orbitofrontal regions because of magnetic field inhomogeneity, a problem that is exacerbated at higher field strengths. In this 7T-fMRI study we compared three methods of improving sensitivity in these areas: parallel transmit, which uses multiple transmit elements, controlled independently, to homogenise the flip angle experienced by the tissue; multi-echo, which entails collection of multiple volumes at different echo times following a single radiofrequency pulse; and multiband, in which multiple slices are acquired simultaneously. We found that parallel transmit and multi-echo increased the magnitude of the BOLD signal change, but only multi-echo increased BOLD magnitude in areas prone to susceptibility artefacts. Multiband and denoising of multi-echo data with independent components analysis (ICA) both improved precision of GLM fit. Exploratory results suggested that multi-echo and ICA denoising can both benefit multivariate analyses. In conclusion, a multi-echo, multiband sequence improved fMRI quality in areas prone to susceptibility artefacts while maintaining sensitivity across the whole brain. We recommend this approach for studies investigating the functional roles of ventral temporal and orbitofrontal regions with 7T fMRI. For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript arising from this work.

Control processes underpinned by the prefrontal cortex are critical for generating task-appropriate behaviour across cognitive domains, yet this region develops extremely late. Traditionally, this developmental pattern is considered negative but necessary. However, an alternative (yet perhaps complementary) view suggests that a developmental period without control could support learning, particularly in the semantic domain. Here, we exploit a recent computational model to test formally whether late development of the context-sensitive use of conceptual knowledge, or ‘semantic control’, would promote concept acquisition. Simulations show that late maturation of semantic control and anatomical connectivity conspire to promote conceptual learning. Delayed control speeds conceptual learning without compromising conceptual representations, particularly when control connects to intermediate layers. To assess whether semantic control also develops late in human children, we conducted a meta-analysis of the classic triadic matching task where participants decide which of two options best matches a third. Matching can be based on taxonomic or thematic relations. When these conflict, participants must exert semantic control to determine which relation is task appropriate. Context-sensitivity develops later than conceptual knowledge with large increases between 3 and 6 years. Thus, the protracted PFC development leads to a delay in acquiring semantic control processes, benefiting conceptual learning.

Understanding neural functioning and plasticity of the brain is a fundamental goal of neuroscience. The ventromedial anterior temporal lobe (ATL) has been suggested as the centre-point of a core transmodal hub for semantic memory, playing a crucial role in the representation of coherent conceptual knowledge. However, non-invasive direct modulation of the ventromedial ATL has remained challenging. Transcranial ultrasound stimulation (TUS) is an emerging neuromodulatory technique that delivers acoustic energy with high spatial precision, making it uniquely suited for targeting deep brain structures non-invasively. In this study, we investigated whether theta-burst TUS (tbTUS) to the ventromedial ATL could enhance semantic memory performance in the adult brain. Using a multimodal neuroimaging approach, magnetic resonance spectroscopy (MRS), functional MRI (fMRI), and voxel-based morphometry (VBM), we assessed tbTUS-induced changes in neurochemical concentrations, functional network connectivity, structural plasticity, and semantic memory performance. Compared to control stimulation (ventricle), tbTUS at the ventromedial ATL significantly improved semantic task performance in healthy individuals. MRS analysis revealed that tbTUS decreased GABA and increased Glx levels, reflecting shifts in excitation-inhibition balance. Additionally, tbTUS increased neurometabolites in the ATL, including NAA, creatine and choline, suggesting enhanced neuronal function and metabolism. fMRI analysis demonstrated that tbTUS reduced task-induced regional activity in the ATL and functionally connected semantic regions, while also enhancing intrinsic and effective connectivity across the semantic network. Structural analysis revealed increased grey matter volume in the ATL following tbTUS compared to control stimulation. These findings provide the first convergent evidence that tbTUS can modulate neurochemistry, functional dynamics, and brain morphology to enhance semantic memory function. Our results highlight TUS as a powerful neuromodulatory tool with potential applications in cognitive enhancement and neurorehabilitation, offering a promising intervention for dementia and neurodegenerative disorders.

In this two-part investigation, we examined whether Alzheimer's disease (AD) phenotypes are distinct clinical entities or represent positions within a graded multidimensional space. First, using a large retrospective dataset of past research participants (n = 413) from memory clinics, we examined the comparative distributions of cognitive performance in people diagnosed with typical amnestic AD (tAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). Secondly, a prospective deep phenotyping study of lvPPA (n = 18) compared to typical AD (n = 9) addressed the following questions: (1) Does the multidimensional cognitive pattern of impairment only emerge in advanced lvPPA, and how does it compare to tAD? (2) Do memory deficits in lvPPA appear in a simple clinic-level cognitive assessment or require in-depth neuropsychological investigation? (3) To what extent is performance on verbal episodic memory attributable to language impairment? (4) Do the patterns of decline in lvPPA and tAD stay categorical or multidimensional over time? We explored the associations between scores derived from a principal component analysis of cognitive measures, and grey matter volumes in key memory- and language-related brain regions, at baseline and longitudinally. The clinic-level assessment revealed similar results in both the prospective and retrospective data: (i) patients showed graded distinctions (e.g., predominant visual versus language impairment in people with PCA versus lvPPA) and overlap (e.g., shared weakness in domains such as memory); and (ii) people with lvPPA and tAD were equally impaired on both verbal and non-verbal memory tests in lvPPA and tAD. Longitudinal assessment showed phenotypic dispersion: (i) people with tAD showed varied patterns of phenotypic differentiation; and (ii) people with lvPPA and lvPPA+ exhibited a multidimensional pattern of decline with decreasing principal component scores and worsening multi-domain cognitive performance. The results of Bayesian linear regressions showed evidence for the association of grey matter volumes in language and memory networks, including the bilateral hippocampi, precuneus, posterior cingulate, and temporo-parietal regions with principal component analysis derived scores. The graded distinctions amongst typical amnestic and atypical (language and visual) phenotypes of AD support the proposal for a transdiagnostic, multidimensional phenotype geometry that spans all AD subtypes. We argue that it is essential to include all AD phenotypes in clinical trials and treatments, with a particular focus on transdiagnostic symptoms, considering their relevance to disease burden and interventions.

A fundamental aspect of neuroscience is understanding neural functioning and plasticity of the brain. The anterior temporal lobe (ATL) is a hub for semantic memory, which generates coherent semantic representations about the world. GABAergic inhibition plays a crucial role in shaping human cognition and plasticity, but it is unclear how this inhibition relates to human semantic memory and its plasticity. Here, we employed a combination of continuous theta burst stimulation (cTBS), MR spectroscopy and fMRI to investigate the role of GABA in semantic memory and its neuroplasticity. Our results demonstrated that the inhibitory cTBS increased regional GABA levels in the ATL and decreased ATL blood-oxygen level-dependent (BOLD) activity during semantic processing. Importantly, changes in GABA levels were strongly associated with changes in regional activity induced by cTBS. These results suggest that GABAergic activity may be the mechanism by which cTBS induces after effects on cortical excitability. Furthermore, individuals with better semantic performance exhibited selective activity in the ATL, attributable to higher concentrations of inhibitory GABA, which can sharpen distributed semantic representations, leading to more precise semantic processing. Our results revealed a non-linear, inverted-U-shape relationship between GABA levels in the ATL and semantic performance, thus offering an explanation for the individual differences in the cTBS effect on task performance. These results provide neurochemical and anatomical specificity in shaping task-related cortical activity and behaviour. Understanding the link between neurochemistry and semantic memory has important implications for understanding individual differences in semantic behaviour and developing therapeutic interventions for patients with semantic impairments.

Apathy is a prevalent and persistent neuropsychiatric syndrome across many neurological disorders, significantly impacting on both patients and caregivers. We systematically quantified discrepancies between self- and caregiver-reported apathy in 335 patients with a variety of diagnoses, frontotemporal dementia (behavioural variant and semantic dementia subtypes), Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Alzheimer's disease dementia, mild cognitive impairment, small vessel cerebrovascular disease, subjective cognitive decline and autoimmune encephalitis. Using the Apathy-Motivation Index (AMI) and its analogous caregiver version (AMI-CG), we found that caregiver-reported apathy consistently exceeded self-reported levels across all conditions. Moreover, self-reported apathy accounted for only 14.1% of the variance in caregiver ratings. This apathy reporting discrepancy was most pronounced in conditions associated with impaired insight, such as behavioural variant frontotemporal dementia, and was significantly correlated with cognitive impairment. Deficits in memory and fluency explained an additional 11.2% of the variance in caregiver-reported apathy, highlighting their crucial role in goal-directed behaviour. Specifically, executive function deficits (e.g., indexed by fluency) and memory impairments may contribute to behavioural inertia or recall of it. These findings highlight the need to integrate patient and caregiver perspectives in apathy assessments, especially for conditions with prominent cognitive impairment. To improve diagnostic accuracy and deepen our understanding of apathy across neurological disorders, we emphasise the need of standardised apathy assessment tools tailored to individuals with cognitive deficits. Understanding the cognitive mechanisms underpinning discordant apathy reporting in dementia might help to inform targeted clinical interventions and reduce caregiver burden.

Behavioural changes are a central feature of frontotemporal dementia (FTD); they occur in both behavioural-variant (bvFTD) and semantic dementia (SD)/semantic-variant primary progressive aphasia subtypes. In this study, we addressed two current clinical knowledge gaps; (i) are there qualitative or clear distinctions between behavioural profiles in bvFTD and SD, and (ii) what are the precise roles of the prefrontal cortex and anterior temporal lobes in supporting social behaviour? Resolving these conundrums is crucial for improving diagnostic accuracy and for the development of targeted interventions to treat challenging behaviours in FTD. Informant questionnaires to assess behavioural changes included the Cambridge Behavioural Inventory-Revised and two targeted measures of apathy and impulsivity. Participants completed a detailed neuropsychological battery to permit investigation of the relationship between cognitive status (including social-semantic knowledge, general semantic knowledge and executive function) with behaviour change in FTD. To explore changes in regional grey matter volume, a subset of patients had structural MRI. Diagnosis-based group comparisons were supplemented by a transdiagnostic approach which encompassed the spectrum of bvFTD, SD and “mixed” or intermediate cases. Such an approach is sensitive to the systematic graded variation in FTD and allows the neurobiological underpinnings of behaviour change to be explored across an FTD spectrum. We found a wide range of behavioural changes across FTD. Although quantitatively more severe on average in bvFTD, as expected, the item-level analyses found no evidence for qualitative differences in behavioural profiles or “behavioural double dissociations” between bvFTD and SD. Comparisons of self and informant ratings revealed strong discrepancies in the perspective of the caregiver versus patient. Logistic regression revealed that neuropsychological measures had better discriminative accuracy for bvFTD versus SD than caregiver-reported behavioural measures. A principal component analysis of all informant questionnaire domains extracted three components, interpreted as reflecting: (1) apathy, (2) challenging behaviours and (3) activities of daily living. More severe apathy in both FTD subtypes was associated with (a) increased levels of impaired executive function and (b) anterior cingulate cortex atrophy. Questionnaire ratings of impaired behaviour did not correlate with either anterior temporal lobe atrophy or degraded social-semantic knowledge. Together, these findings highlight the presence of a wide range of behavioural changes in both bvFTD and SD, which vary by degree rather than quality. We recommend a transdiagnostic approach for future studies of the neuropsychological and neuroanatomical underpinnings of behavioural deficits in FTD.

Our study highlights cognitive measures underlying post-stroke recovery using the 'Birmingham Cognitive Screening' (BCOS) program, the only dataset with comprehensive assessments of cognition, praxis, and stroke outcomes. We analysed 256 stroke patients tested for cognitive deficits, which uniquely included apraxia and the Barthel Index for daily living activities at subacute and chronic stages. Using step-wise multivariate linear regression, we identified significant predictive factors: praxis, language, orientation, and baseline independence linked to improved daily activities, and validated our model with 4-fold cross-validation. This research underscores the vital role of specific cognitive measures including apraxia as key cognitive predictors for stroke recovery.

Impaired phonological short-term memory is a core feature of the logopenic variant of primary progressive aphasia (lvPPA), but it is not clear whether a core phonological processing deficit is also present. We asked three questions: (i) beyond short-term memory impairment, do people with lvPPA have an impairment within phonology itself?; (ii) is their performance in working memory and confrontation naming reflective of this phonological impairment and/or other key contributing deficits (e.g., semantic)?; and (iii) is their repetition performance related to structural and functional differences in key language-dominant regions? We compared non-word and word repetition and short-term memory performance in patients with typical, amnestic Alzheimer's disease (tAD, n = 9), lvPPA per consensus criteria (n = 10), and others who previously satisfied definitions of lvPPA but had progressed with multi-domain cognitive impairments (lvPPA+, n = 8). Bayesian analyses revealed no group differences in phonological tasks of word and non-word repetition. There was, however, a very strong group effect on multi-syllabic word/phrase repetition. We found very strong evidence for an effect of self-reported hearing loss on both word and non-word repetition, but not multi-syllabic word/phrase repetition. A comparison of phonological (as indexed by non-word repetition) versus working memory (as measured by multisyllabic word repetition and digit span) and confrontation naming tasks produced either no evidence or evidence for no correlation. Confrontation naming correlated positively with multisyllabic word/phrase repetition and semantic assessments across the whole group. Beyond the expected grey matter reductions in patients relative to controls in the left posterior superior temporal gyrus, anterior temporal lobe, and inferior temporal gyrus, we found no evidence for the associations between non-word repetition and functional connectivity between all regions of interest in the whole group. When excluding controls, the only anecdotal evidence that was corroborated by frequentist multiple regression was for an association between non-word repetition and functional connectivity between dorsal premotor and posterior superior temporal gyrus after controlling for the grey matter volumes in these regions. We have shown that deficits in "pure" phonological tasks, namely single word and non-word repetition, are (i) not dependent on working memory and (ii) greater in patients with a self-reported hearing loss across all groups with lvPPA or tAD. Our results suggest that instead of having a core phonological impairment, lvPPA patients have a working memory/buffering impairment that adversely affects their performance on length-dependent working memory tasks.