Biology subjects

Baker, A. M.

Publications and source records attributed to Baker, A. M..

7 recordsLinked to original sources

bioRxiv2026

Extent of damage to descending output from cortex rather than to specific cortical regions drives the emergence of flexor synergy in non-human primates

Obligate flexor synergies are a defining feature of the hemiparetic phenotype following stroke in humans. Although these intrusive synergies can diminish over time, recovery may plateau, leaving some individuals with movements permanently constrained to synergies. Despite their clinical significance, the neural mechanisms underlying the emergence and persistence of abnormal synergies remain poorly understood. To investigate this mechanistically, three macaque monkeys were trained on a reach and grasp task prior to receiving one of three unilateral lesion types: 1) a focal sensorimotor cortical lesion, 2) a combined sensorimotor cortical and magnocellular red nucleus (RNm) lesion, or 3) a lesion of the internal capsule. Upper limb three-dimensional kinematics and EMG cross correlation were used to measure the intrusion of synergies during in synergy vs out of synergy reaching. A combined RNm and cortical lesion produced weakness but no flexor synergy. A similar-sized cortical lesion generated mild synergies which substantially recovered. By contrast, a large internal capsule lesion produced severe, persistent flexor synergy. Collectively, these findings suggest that the emergence of abnormal synergies is determined by the extent of corticofugal disruption, and their persistence depends on the ability of surviving supraspinal motor pathways to regain selective control over muscle contractions.

neuroscience↗

bioRxiv2025

Kinematic Dissection of Arm Paresis after Focal New M1, Old M1 and Red Nucleus Lesions in Non-Human Primates

Cortical and subcortical lesions to the motor system, as often occur with stroke, typically lead to transitions through a stereotyped upper limb recovery sequence. After initial weakness and loss of dexterity, spasticity and fixed muscle coactivation patterns (synergies) appear. Early work suggested that different features arise from distinct primary motor cortex (M1) subdivisions. Here we investigated this with modern methods, using ischemic lesions of various cortical areas and electrocoagulation lesions of magnocellular red nucleus (RNm) in rhesus monkeys. Nine animals were trained on a reach and grasp task; hand kinematics were assessed with markerless tracking. The proportion of damaged cortical layer V cells in each cortical area was quantified, and corresponding kinematic effects evaluated. Reaching speed showed greater and more persistent reductions with larger lesions to the posterior part of M1 on the gyrus (Posterior Old M1 in Stricks terminology). Initial increases in trajectory variability were more consistent with greater damage within the central sulcus (New M1); these partially recovered. Lesions involving Anterior Old M1 (Area 4s in Hines terminology) had no additive negative effects. An extensive cortical lesion, which combined New and Old M1 with pre-motor and somatosensory cortex damage did not produce a worse or more persistent deficit than lesions limited to M1, suggesting that loss of arm control arose mainly from damage to descending pathways rather than cortico-cortical interactions. Lesions of RNm led to long-lasting slowing of reach, but no increase in variability. Subsequent cortical lesions to Old M1 led to more severe effects, and worse recovery, than without the preceding RNm lesion. This suggests an important neural compensatory role for the rubrospinal tract following cortical damage in monkey, which is not available in humans where the rubrospinal tract is vestigial. None of the lesions investigated led to overt abnormal synergies. The results are consistent with known differences in descending connections from each area: New M1 has fast cortico-motoneuronal output, known to be important for fine motor control (here assessed by trajectory variability); Old M1 has cortico-reticular connections able to activate the reticulospinal tract, important for generating the high forces needed for fast movements.

neuroscience↗

bioRxiv2025

A spinal origin for the obligate flexor synergy in the non-human primate: Implications for control of reaching

Stroke survivors frequently develop the flexor synergy, an obligate co-contraction of shoulder abductors and elbow flexors; the neural substrate has proven elusive. Here we trained healthy monkeys to generate isometric elbow and shoulder torques to move an on-screen cursor, and recorded neuron firing from motor cortical areas and the reticular formation. In all regions we found cells correlated with activity around a single joint. Neurons coding co-contractions showed a bias towards combinations orthogonal to the post-stroke flexor synergy, e.g. shoulder abduction with elbow extension. Threshold microstimulation in the spinal cord but not in either motor cortex or the reticular formation generated coactivation aligned to the flexor synergy. We suggest the evolution of prehension required descending systems either to control or bypass locomotion-dedicated spinal circuits. Loss of descending input after stroke constrains the upper limb to spinal synergies best suited to primitive locomotor functions.

neuroscience↗

bioRxiv2025

High-density, Identified Cell Recordings from Motor Cortex of Awake Behaving Macaques using 1024-channel SiNAPS-NHP Probes

Objective/BackgroundAcquiring bioelectric signals from many single neurons in primate brain remains challenging. Chronic implants offer a reasonable channel count ([~]100) but sample only a small, fixed region of the cortex. Acutely inserted electrodes can sample from a wider region by making new penetrations each day. The aim of this study was to develop an active dense CMOS probe and experimental procedures to demonstrate acute large-scale single unit recordings from behaving monkeys. MethodsA single-shank CMOS probe was specifically designed for intracortical macaque recordings. The device is based on SiNAPS technology, with additional multiplexing circuits to minimize output lines. Synchronous sampling at 20 kHz/channel from >2k electrode-pixels is achieved with multiple probe systems. Experiments were performed in behaving macaques, achieving multiple day insertions in the motor cortex. Methods were developed to extract spontaneous spiking times of antidromically-identified neurons. ResultsThe probe (10.7 mm in length, 158 m in width, 50 m in thickness) provides a regular array of 1024 electrodes (14 x 14 m2) arranged in 4 columns with an interelectrode pitch of 30 m. Dural penetration is eased by a small pilot hole; the optimized insertion procedure allows recordings from many different sites. Some cells were identified by antidromic activation as pyramidal tract neurons, which project to the spinal cord. ConclusionThis probe configuration can reach the anterior bank of the central sulcus, which contains many corticospinal cells that connect directly to motoneurons. SignificanceThis study is an important advance in the toolkit of primate neurophysiology.

neuroscience↗

bioRxiv2021

Using 3D geometric morphometrics to aid taxonomic and ecological understanding of a recent speciation event within a small Australian marsupial (genus Antechinus)

Taxonomic distinction of species forms the foundation of biodiversity assessments and conservation priorities. However, traditional morphological and/or genetics-based taxonomic assessments frequently miss the opportunity of elaborating on the ecological and functional context of species diversification. Here, we used 3D geometric morphometrics of the cranium to improve taxonomic differentiation and add eco-morphological characterisation of a young cryptic divergence within the marsupial carnivorous genus Antechinus. Specifically, we used 168 museum specimens to characterise the recently proposed clades A. stuartii "south", A. stuartii "north" and A. subtropicus. Beyond slight differences attributable to overall size (and therefore not necessarily diagnostic), we also found clear allometry-independent shape variation. This allowed us to define new, easily measured diagnostic traits in the palate, which differentiate the three clades. Contrary to previous suggestions, we found no support for a latitudinal gradient as causing the differentiation between the clades. However, skull shape co-varied with temperature and precipitation seasonality, suggesting that the clades may be adapted to environmental variables that are likely to be impacted by climate change. Our study demonstrates the use of 3D geometric morphometrics to improve taxonomic diagnosis of cryptic mammalian species, while providing perspectives on the adaptive origins and potential future threats of mammalian diversity.

zoology↗

bioRxiv2019

Macrophage-mediated immunoediting drives ductal carcinoma evolution: Space is the game changer

Under normal conditions, the immune system is capable of rapidly detecting and eliminating potentially dangerous entities, including tumor cells. Due to intense selection pressure imposed by the immune response, tumor cells often evolve strategies to avoid elimination in a process known as immunoediting. It is less known how the evolutionary response to immune predation is altered by context. We explore the evolution of immune escape strategies in ductal cancers, a natural case in which to study evolution in different contexts: inside and outside of ducts. We highlight the role of macrophages as a source of \"public goods,\" releasing diffusible factors (reactive oxygen species and growth factors). Immunohistochemistry reveals differences between macrophage densities of invasive ductal carcinomas and non-invasive ductal carcinomas in situ. For the first time, immunohistochemistry (IHC) imaging data comparing DCIS to IDC were used to initialize mechanistic agent-based models of evolutionary dynamics. By using IHC to map the initial conditions of a growing tumor, we show that spatial competition and structure influence transient dynamics during invasion. These dynamics are context-dependent, a conclusion that may be missed from interpreting imaging or non-spatial modeling alone. Before invasion, the presence of macrophages correlate with shorter ductal breach times. After invasion, tumors may employ a \"pioneer-engineer\" strategy where pioneering immunoresistant cells on the tumors edge stimulate the release of M1-macrophage-derived reactive oxygen species, degrading surrounding stroma. Behind the invasive edge, the engineering immunosuppressive cells promote the release of M2-macrophage-derived growth factors, providing a long-term immune escape strategy. Together, mathematical modeling and image analysis highlight the crucial role tumor-associated macrophages play in immune escape and invasion, both inside and outside of ducts.

cancer biology↗

bioRxiv2017

Defining Depression Cohorts Using the EHR: Multiple Phenotypes Based on ICD-9 Codes and Medication Orders

BackgroundMajor Depressive Disorder (MDD) is one of the most common mental illnesses and a leading cause of disability worldwide. Electronic Health Records (EHR) allow researchers to conduct unprecedented large-scale observational studies investigating MDD, its disease development and its interaction with other health outcomes. While there exist methods to classify patients as clear cases or controls, given specific data requirements, there are presently no simple, generalizable, and validated methods to classify an entire patient population into varying groups of depression likelihood and severity. MethodsWe have tested a simple, pragmatic electronic phenotype algorithm that classifies patients into one of five mutually exclusive, ordinal groups, varying in depression phenotype. Using data from an integrated health system on 278,026 patients from a 10-year study period we have tested the convergent validity of these constructs using measures of external validation, including patterns of psychiatric prescriptions, symptom severity, indicators of suicidality, comorbidity, mortality, health care utilization, and polygenic risk scores for MDD. ResultsWe found consistent patterns of increasing morbidity and/or adverse outcomes across the five groups, providing evidence for convergent validity. LimitationsThe study population is from a single rural integrated health system which is predominantly white, possibly limiting its generalizability. ConclusionOur study provides initial evidence that a simple algorithm, generalizable to most EHR data sets, provides categories with meaningful face and convergent validity that can be used for stratification of an entire patient population.

epidemiology↗