In the back of your mind: Cortical mapping of tactile and proprioceptive paraspinal afferent inputs

Persistent pain alters brain-body representations, highlighting their potential pathological significance. In chronic low back pain (LBP), sparse evidence points towards a shift of the cortical representation of sensory afferents of the back. However, systematic investigations of the cortical representation of tactile and proprioceptive paraspinal afferents along the thoracolumbar axis are lacking. Detailed cortical maps of paraspinal afferent input might be crucial to further explore potential relationships between brain changes and the development and maintenance of chronic LBP. We therefore validated a novel and functional magnetic resonance imaging- (fMRI-)compatible method of mapping cortical representations of tactile and proprioceptive afferents of the back, using pneumatic vibrotactile stimulation ("pneuVID") at varying frequencies and paraspinal locations, in conjunction with high-resolution fMRI. We hypothesised that: (i) high (80 Hz) frequency stimulation would lead to increased postural sway compared to low (20 Hz) stimulation, due to differential evoked mechanoreceptor contributions to postural control (proprioceptive vs tactile); and (ii) that high (80 Hz) versus low (20 Hz) frequency stimulation would be associated with neuronal activity in distinct primary somatosensory (S1) and motor (M1) cortical targets of tactile and proprioceptive afferents (N=15, healthy volunteers). Additionally, we expected neural representations to vary spatially along the thoracolumbar axis. We found significant differences between neural representations of low and high frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral sensorimotor cortical regions. Proprioceptive (80 Hz) stimulation preferentially activated sub-regions S1 3a and M1 4p, while tactile (20 Hz) stimulation was more encoded in S1 3b and M1 4a. Moreover, in S1, lower back proprioceptive stimulation activated dorsal-posterior representations, compared to ventral-anterior representations activated by upper back stimulation. As per our hypotheses, we found distinct sensorimotor cortical tactile and proprioceptive representations, with the latter displaying clear topographic differences between the upper and lower back. This thus represents the first behavioural and neurobiological validation of the novel pneuVID method for stimulating muscle spindles and mapping cortical representations of paraspinal afferents. Future investigations of detailed cortical maps will be of major importance in elucidating the role of cortical reorganization in the pathophysiology of chronic LBP.

Learning enhances behaviorally relevant representations in apical dendrites

Learning alters cortical representations and improves perception. Apical tuft dendrites in Layer 1, which are unique in their connectivity and biophysical properties, may be a key site of learning-induced plasticity. We used both two-photon and SCAPE microscopy to longitudinally track tuft-wide calcium spikes in apical dendrites of Layer 5 pyramidal neurons as mice learned a tactile behavior. Mice were trained to discriminate two orthogonal directions of whisker stimulation. Reinforcement learning, but not repeated stimulus exposure, enhanced tuft selectivity for both directions equally, even though only one was associated with reward. Selective tufts emerged from initially unresponsive or low-selectivity populations. Animal movement and choice did not account for changes in stimulus selectivity. Enhanced selectivity persisted even after rewards were removed and animals ceased performing the task. We conclude that learning produces long-lasting realignment of apical dendrite tuft responses to behaviorally relevant dimensions of a task.

Lateral entorhinal cortex suppresses drift in cortical memory representations.

Memory retrieval is thought to depend on the reinstatement of cortical memory representations guided by pattern completion processes in the hippocampus. The lateral entorhinal cortex (LEC) is one of the intermediary regions supporting hippocampal-cortical interactions and houses neurons that prospectively signal past events in a familiar environment. To investigate the functional relevance of the LEC's activity for cortical reinstatement, we pharmacologically inhibited the LEC and examined its impact on the stability of ensemble firing patterns in one of the LEC's efferent targets, the medial prefrontal cortex (mPFC). When male rats underwent multiple epochs of identical stimulus sequences in the same environment, the mPFC maintained a stable ensemble firing pattern across repetitions, particularly when the sequence included pairings of neutral and aversive stimuli. With LEC inhibition, the mPFC still formed an ensemble pattern that accurately captured stimuli and their associations within each epoch. However, LEC inhibition markedly disrupted its consistency across the epochs by decreasing the proportion of mPFC neurons that stably maintained firing selectivity for stimulus associations. Thus, the LEC stabilizes cortical representations of learned stimulus associations, thereby facilitating the recovery of the original memory trace without generating a new, redundant trace for familiar experiences. Failure of this process might underlie retrieval deficits in conditions associated with degeneration of the LEC, such as normal aging and Alzheimer's disease.

Influence of different transcranial magnetic stimulation current directions on the corticomotor control of lumbar erector spinae muscles during a static task

Different directions of transcranial magnetic stimulation (TMS) can activate different neuronal circuits. While posteroanterior current (PA-TMS) depolarizes mainly interneurons in primary motor cortex (M1), an anteroposterior current (AP-TMS) has been suggested to activate different M1 circuits and perhaps axons from the premotor regions. Although M1 is also involved in the control of axial muscles, no study has explored if different current directions activate different M1 circuits that may have distinct functional role. The aim of the study was to compare the effect of different current directions (PA- and AP-TMS) on the corticomotor control and spatial cortical organisation of the lumbar erector spinae muscle (LES). Thirthy-four healthy participants were recruited for two independent experiments and LES motor-evoked potentials (MEP) were recorded. In experiment 1 (n=17), active motor threshold (AMT), MEP latencies, recruitment curve (90 to 160% AMT), excitatory and inhibitory intracortical mechanisms using paired-pulse TMS (80% followed by 120% AMT stimuli at 2-3-10 and 15ms inter-stimulus intervals) were tested using a double cone (n=12) and a figure-of-eight (n=5) coils. In experiment 2 (n=17), LES cortical representations were tested using PA- and AP-TMS. AMT was higher for AP- compared to PA-TMS (p=0.002). Longer latencies with AP-TMS were compared to PA-TMS (p=0.017). AP-TMS produced more inhibition compared to PA-TMS at 2ms and 3ms (p=0.010), but no difference was observed for longer intervals. No difference was found for recruitment curve and mapping. Those findings suggest that each PA- and AP-TMS may activate different cortical circuits controlling low back muscles as proposed for hand muscles.

Transformation of Primary Sensory Cortical Representations from Layer 4 to Layer 2

Sensory input arrives from thalamus in cortical layer (L) 4, from which it flows predominantly to superficial layers, so that L4 to L2 constitutes one of the earliest cortical feedforward networks. Despite extensive study, the transformation performed by this network remains poorly understood. We use two-photon calcium imaging in L2-4 of primary vibrissal somatosensory cortex (vS1) to record neural activity as mice perform an object localization task with two whiskers. We find that touch responses sparsen but become more reliable from L4 to L2, with superficial neurons responding to a broader range of touches. Decoding of sensory features either improves from L4 to L2 or remains unchanged. Pairwise correlations increase superficially, with L2/3 containing ensembles of mostly broadly tuned neurons responding robustly to touch. Thus, from L4 to L2, cortex transitions from a dense probabilistic code to a sparse and robust ensemble-based code that improves stimulus decoding, facilitating perception.

Linking Individual Differences in Personalized Functional Network Topography to Psychopathology in Youth

The spatial layout of large-scale functional brain networks differs between individuals and is particularly variable in association cortex that has been implicated in a broad range of psychiatric disorders. However, it remains unknown whether this variation in functional topography is related to major dimensions of psychopathology in youth. Capitalizing on a large sample with 27-minutes of high-quality functional MRI data (n=790, ages 8-23 years) and advances in machine learning, we examined associations between functional topography and four correlated dimensions of psychopathology (fear, psychosis, externalizing, anxious-misery) as well as an overall psychopathology factor. We found that functional topography significantly predicted individual differences in dimensions of psychopathology, driven mainly by robust associations between topography and overall psychopathology. Reduced cortical representations of association networks were among the most important features of the model. Our results emphasize the value of considering systematic differences in functional neuroanatomy for personalized diagnostics and therapeutics in psychiatry.

Neural Correlates of Individual Differences in Speech Categorization: Evidence from Subcortical, Cortical, and Behavioral Measures

Categorization is a fundamental cognitive ability to group different objects as the same. This ability is particularly indispensable for human speech perception, yet individual differences in speech categorization are nonetheless ubiquitous. The present study investigates the neurophysiological mechanisms underlying the variability in categorization of voice-onset time (VOT). Subcortical and cortical speech-evoked responses are recorded to investigate speech representations at two functional levels of auditory processing. Individual differences in psychometric functions correlate positively with how faithfully subcortical responses encode VOT differences. Moreover, individuals also differ in how strongly the subcortical and cortical representations correlate with each other. Listeners with gradient categorization show higher correspondences between the two representations, indicating that acoustic information is relayed faithfully from the subcortical to the cortical level; listeners with discrete categorization exhibit decreased similarity between the two representations, suggesting that the subcortical acoustic encoding is transformed at the cortical level to reflect phonetic category information.

Thalamic state controls timing and synchronization of primary somatosensory cortical representations in the awake mouse

The thalamus controls transmission of sensory signals from periphery to cortex, ultimately shaping perception. Despite this significant role, dynamic thalamic gating and the consequences for downstream cortical sensory representations have not been well studied in the awake brain. We optogenetically modulated the ventro-posterior medial thalamus in the vibrissa pathway of the awake mouse, and measured spiking activity in the thalamus, and at the level of primary somatosensory cortex (S1) using extracellular electrophysiology and genetically encoded voltage imaging. Thalamic hyperpolarization significantly amplified thalamic sensory-evoked spiking through enhanced bursting, yet surprisingly the S1 cortical response was not amplified, but instead timing precision was significantly increased, spatial activation more focused, and there was an increased synchronization of cortical inhibitory neurons. A thalamocortical network model implicates the precise timing of feedforward thalamic spiking, and timing-sensitive engagement of synaptic depression, presenting a highly sensitive, state-dependent timing-based gating of sensory signaling to cortex.

Neural Correlates of Attentional Modulation of Prepulse Inhibition

Prepulse inhibition (PPI) refers to the suppression of the startle reflex when the intense startling stimulus is shortly (20–500 ms) preceded by a weak non-startling stimulus (prepulse). Although the main neural correlates of PPI lie in the brainstem, previous research has revealed that PPI can be top-down modulated by attention. However, in the previous attend-to-prepulse PPI paradigm, only continuous prepulse but not discrete prepulse (20 ms) could elicit attentional modulation of PPI. Also, the relationship between the attentional enhancement of PPI and the changes in early cortical representations of prepulse signals is unclear. This study develops a novel attend-to-prepulse PPI task, when the discrete prepulse is set at 150 ms at a lead interval of 270 ms, and reveals that the PPI with attended prepulse is larger than the PPI with ignored prepulse. In addition, the early cortical representations (N1/P2 complex) of the prepulse show dissociation between the attended and ignored prepulse. N1 component is enhanced by directed attention, and the attentional increase of the N1 component is positively correlated with the attentional enhancement of PPI, whereas the P2 component is not affected by attentional modulation. Thus, directed attention to the prepulse can enhance both PPI and the early cortical representation of the prepulse signal (N1).