Neurochemical predictors of generalised learning induced by brain stimulation and training.

Methods of cognitive enhancement for humans are most impactful when they generalise across tasks. However, the extent to which such "transfer" is possible via interventions is widely debated. In addition, the contribution of excitatory and inhibitory processes to such transfer is unknown. Here, in a large-scale neuroimaging individual differences study with humans (both sexes), we paired multitasking training and non-invasive brain stimulation (transcranial direct current stimulation; tDCS) over multiple days and assessed performance across a range of paradigms. In addition, we varied tDCS dosage (1.0 mA and 2.0 mA), electrode montage (left or right prefrontal regions), and training task (multitasking versus a control task) and assessed GABA and glutamate concentrations via ultra-high field 7T magnetic resonance spectroscopy. Generalised benefits were observed in spatial attention, indexed by visual search performance, when multitasking training was combined with 1.0 mA stimulation targeting either the left or right prefrontal cortex. This transfer effect persisted for ∼30 days post-intervention. Critically, the transferred benefits associated with right prefrontal tDCS were predicted by pre-training concentrations of glutamate in the prefrontal cortex. Thus, the effects of this combined stimulation and training protocol appears to be linked predominantly to excitatory brain processes.Significance statement Despite the general public's fascination with cognitive training, performance benefits rarely extend beyond the trained task, i.e., 'transfer'. Our study examines the impact of combining executive function training and transcranial direct current stimulation (tDCS) on human cognitive performance and identifies a functional neural metabolite marker (glutamate concentrations in prefrontal cortex assessed via 7 T MR Spectroscopy) that predicts outcomes. In the largest study of its kind to date (178 individuals), we find generalised performance benefits induced by frontal tDCS for an untrained spatial attention task. Further, the degree of transfer correlated with concentrations of glutamate in the frontal cortex. Thus, excitatory neural processes in this region are implicated in the transfer of paired stimulation and training benefits.

Neurodesk: an accessible, flexible and portable data analysis environment for reproducible neuroimaging.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.

Individual Differences in Decision Strategy Relate to Neurochemical Excitability and Cortical Thickness.

The speed-accuracy trade-off (SAT), whereby faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during the performance of almost all daily tasks. To date, computational modeling has implicated the latent decision variable of response caution (thresholds), the amount of evidence required for a decision to be made, in the SAT. Previous imaging has associated frontal regions, notably the left prefrontal cortex and the presupplementary motor area (pre-SMA), with the setting of such caution levels. In addition, causal brain stimulation studies, using transcranial direct current stimulation (tDCS), have indicated that while both of these regions are involved in the SAT, their role appears to be dissociable. tDCS efficacy to impact decision-making processes has previously been linked with neurochemical concentrations and cortical thickness of stimulated regions. However, to date, it is unknown whether these neurophysiological measures predict individual differences in the SAT, and brain stimulation effects on the SAT. Using ultra-high field (7T) imaging, here we report that instruction-based adjustments in caution are associated with both neurochemical excitability (the balance between GABA+ and glutamate) and cortical thickness across a range of frontal regions in both sexes. In addition, cortical thickness, but not neurochemical concentrations, was associated with the efficacy of left prefrontal and superior medial frontal cortex (SMFC) stimulation to modulate performance. Overall, our findings elucidate key neurophysiological predictors, frontal neural excitation, of individual differences in latent psychological processes and the efficacy of stimulation to modulate these.SIGNIFICANCE STATEMENT The speed-accuracy trade-off (SAT), faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during most daily tasks. The SAT is often investigated by explicitly instructing participants to prioritize speed or accuracy when responding to stimuli. Using ultra-high field (7T) magnetic resonance imaging (MRI), we found that individual differences in the extent to which participants adjust their decision strategies with instruction related to neurochemical excitability (ratio of GABA+ to glutamate) and cortical thickness in the frontal cortex. Moreover, brain stimulation to the left prefrontal cortex and the superior medial frontal cortex (SMFC) modulated performance, with the efficacy specifically related to cortical thickness. This work sheds new light on the neurophysiological basis of decision strategies and brain stimulation.

HumanBrainAtlas: an in vivo MRI dataset for detailed segmentations.

We introduce HumanBrainAtlas, an initiative to construct a highly detailed, open-access atlas of the living human brain that combines high-resolution in vivo MR imaging and detailed segmentations previously possible only in histological preparations. Here, we present and evaluate the first step of this initiative: a comprehensive dataset of two healthy male volunteers reconstructed to a 0.25 mm isotropic resolution for T1w, T2w, and DWI contrasts. Multiple high-resolution acquisitions were collected for each contrast and each participant, followed by averaging using symmetric group-wise normalisation (Advanced Normalisation Tools). The resulting image quality permits structural parcellations rivalling histology-based atlases, while maintaining the advantages of in vivo MRI. For example, components of the thalamus, hypothalamus, and hippocampus are often impossible to identify using standard MRI protocols-can be identified within the present data. Our data are virtually distortion free, fully 3D, and compatible with the existing in vivo Neuroimaging analysis tools. The dataset is suitable for teaching and is publicly available via our website (hba.neura.edu.au), which also provides data processing scripts. Instead of focusing on coordinates in an averaged brain space, our approach focuses on providing an example segmentation at great detail in the high-quality individual brain. This serves as an illustration on what features contrasts and relations can be used to interpret MRI datasets, in research, clinical, and education settings.

Neurodesk: An accessible, flexible, and portable data analysis environment for reproducible neuroimaging.

Neuroimaging data analysis often requires purpose-built software, which can be challenging to install and may produce different results across computing environments. Beyond being a roadblock to neuroscientists, these issues of accessibility and portability can hamper the reproducibility of neuroimaging data analysis pipelines. Here, we introduce the Neurodesk platform, which harnesses software containers to support a comprehensive and growing suite of neuroimaging software (https://www.neurodesk.org/). Neurodesk includes a browser-accessible virtual desktop environment and a command line interface, mediating access to containerized neuroimaging software libraries on various computing platforms, including personal and high-performance computers, cloud computing and Jupyter Notebooks. This community-oriented, open-source platform enables a paradigm shift for neuroimaging data analysis, allowing for accessible, flexible, fully reproducible, and portable data analysis pipelines.

Lower hypothalamic volume with lower body mass index is associated with shorter survival in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS. METHODS: We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS (n = 42), patients with AD (n = 167) and non-neurodegenerative disease controls (n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes. RESULTS: Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association; probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite (p = 0.58) or hypermetabolism (p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight (p = 0.08) and fat mass (p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07). CONCLUSION: These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and  is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death.

Enhanced semantic memory in a case of highly superior autobiographical memory.

Highly superior autobiographical memory (HSAM) is characterised by the ability to recall personal events, dates, and news events from long-term memory with profound detail and accuracy. Anecdotes from these individuals suggest that retrieval of rich autobiographical detail is automatic, and often intrusive rather than effortful. We created two novel experiments to objectively verify whether retrieval of information reflects serial or parallel processing in a case of HSAM (R.S.), who has a self-reported superior memory for two sources of personally relevant information: (a) the ability to name days of the week for any given calendar date since the year 2000; and (b) the ability to remember the entire text, practically word-for-word, of the seven Harry Potter books. RS and 10 age-matched controls, who were also aficionados of the Harry Potter series, were presented with pairs of calendar dates or sentences and asked, "Which date came earlier in the week?" or "Which sentence came earlier in the book?" Items within a pair varied in the proximity to one another in time. RS correctly identified earlier calendar dates and sentences with near perfect accuracy, and her reaction time was not impacted by the temporal distance between items. Controls were unable to identify earlier calendar dates and their accuracy and reaction time was dependent on the temporal distance of items. Structural magnetic resonance imaging (MRI) comparing RS with a normative dataset found no significant differences in any memory-related brain regions. Our findings suggest that HSAM memory retrieval for stored information largely reflects parallel processing, rather than a temporal-based system. We also discovered that RS has superior memory for semantic information, boosted by reportedly attaching autobiographical memories to these details. This unusual HSAM phenomenon may hold further clues to creating strong and lasting memories, which appear to be uniquely rich in detail.

Towards Optimising MRI Characterisation of Tissue (TOMCAT) Dataset including all Longitudinal Automatic Segmentation of Hippocampal Subfields (LASHiS) data.

Seven healthy participants were scanned using a Siemens Magnetom 7 Tesla (T) whole-body research MRI scanner (Siemens Healthcare, Erlangen, Germany). The first scan session was acquired in 2016 (time point one), the second and third session in 2019 (time point two and three, respectively) with the third session acquired 45 min following the second as a scan-rescan condition. The following scans were acquired for all time points: structural T1 weighted (T1w) MP2RAGE, high in-plane resolution Turbo-Spin Echo (TSE) dedicated for hippocampus subfield segmentation. The data were used in three projects to date, for more insight see: 1) Non-linear realignment for Turbo-Spin Echo retrospective motion correction and hippocampus segmentation improvement [1] 2) Longitudinal Automatic Segmentation of Hippocampal Subfields (LASHiS) using multi-contrast MRI [2]. 3) The challenge of bias-free coil combination for quantitative susceptibility mapping at ultra-high field [3]. Data were converted from DICOM to nifti format following the Brain Imaging Data Structure (BIDS) [4]. Data were analysed for the accompanying manuscript "Longitudinal Automatic Segmentation of Hippocampal Subfields (LASHiS) using multi-contrast MRI" including test-retest reliability and longitudinal Bayesian Linear Mixed Effects (LME) modelling.

Dissociable effects of tDCS polarity on latent decision processes are associated with individual differences in neurochemical concentrations and cortical morphology.

Applying a weak electrical current to the cortex has the potential to modulate neural functioning and behaviour. The most common stimulation technique, transcranial direct current stimulation (tDCS), has been used for causal investigations of brain and cognitive functioning, and to treat psychiatric conditions such as depression. However, the efficacy of tDCS in modulating behaviour varies across individuals. Moreover, despite being associated with different neural effects, the two polarities of electrical stimulation - anodal and cathodal - can result in similar behavioural outcomes. Here we employed a previously replicated behavioural paradigm that has been associated with polarity non-specific disruption of training effects in a simple decision-making task. We then used the linear ballistic accumulator model to quantify latent components of the decision-making task. In addition, magnetic resonance imaging measures were acquired prior to tDCS sessions to quantify cortical morphology and local neurochemical concentrations. Both anodal and cathodal stimulation disrupted learning-related task improvement relative to sham (placebo) stimulation, but the two polarities of stimulation had distinct effects on latent task components. Whereas anodal stimulation tended to affect decision thresholds for the behavioural task, cathodal stimulation altered evidence accumulation rates. Moreover, performance variability with anodal stimulation was related to cortical thickness of the inferior frontal gyrus, whereas performance variability with cathodal stimulation was related to cortical thickness in the inferior precentral sulcus, as well as to prefrontal neurochemical excitability. Our findings demonstrate that both cortical morphology and local neurochemical balance are important determinants of individual differences in behavioural responses to electrical brain stimulation.

Non-linear realignment improves hippocampus subfield segmentation reliability.

Participant movement can deleteriously affect MR image quality. Further, for the visualization and segmentation of small anatomical structures, there is a need to improve image quality, specifically signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), by acquiring multiple anatomical scans consecutively. We aimed to ameliorate movement artefacts and increase SNR in a high-resolution turbo spin-echo (TSE) sequence acquired thrice using non-linear realignment in order to improve segmentation consistency of the hippocampus subfields. We assessed the method in 29 young healthy participants, 11 Motor Neuron Disease patients, and 11 age matched controls at 7T, and 24 healthy adolescents at 3T. Results show improved image segmentation of the hippocampus subfields when comparing template-based segmentations with individual segmentations with Dice overlaps N = 75; ps < 0.001 (Friedman's test) and higher sharpness ps < 0.001 in non-linearly realigned scans as compared to linearly, and arithmetically averaged scans.

The efficacy of transcranial direct current stimulation to prefrontal areas is related to underlying cortical morphology.

Applying a weak electrical current to the cortex can have effects on a range of behaviours. Techniques such as transcranial direct current stimulation (tDCS) have been widely used in both research and clinical settings. However, there is significant variability across individuals in terms of their responsiveness to stimulation, which poses practical challenges to the application of tDCS, but also provides a unique opportunity to study the link between the brain and behaviour. Here, we assessed the role of individual differences in cortical morphology - specifically in prefrontal cortical regions of interest - for determining the influence of tDCS on decision-making performance. Specifically, we employed magnetic resonance imaging (MRI) and a previously replicated paradigm in which we modulated learning in a simple decision-making task by applying tDCS to the left prefrontal cortex in human subjects of both sexes. Cortical thickness of the left (but not right) prefrontal cortex accounted for almost 35% of the variance in stimulation efficacy across subjects. This is the first demonstration that variations in cortical architecture are associated with reliable differences in the effects of tDCS on cognition. Our findings have important implications for predicting the likely efficacy of different non-invasive brain stimulation treatments on a case by case basis.