Multiplexed Subspaces Route Neural Activity Across Brain-wide Networks.

Cognition is flexible. Behaviors can change on a moment-by-moment basis. Such flexibility is thought to rely on the brain's ability to route information through different networks of brain regions in order to support different cognitive computations. However, the mechanisms that determine which network of brain regions is engaged are unknown. To address this, we combined cortex-wide calcium imaging with high-density electrophysiological recordings in eight cortical and subcortical regions of mice. Different dimensions within the population activity of each brain region were functionally connected with different cortex-wide 'subspace networks' of regions. These subspace networks were multiplexed, allowing a brain region to simultaneously interact with multiple independent, yet overlapping, networks. Alignment of neural activity within a region to a specific subspace network dimension predicted how neural activity propagated between regions. Thus, changing the geometry of the neural representation within a brain region could be a mechanism to selectively engage different brain-wide networks to support cognitive flexibility.

Perineuronal Nets in the Dorsomedial Striatum Contribute to Behavioral Dysfunction in Mouse Models of Excessive Repetitive Behavior.

Background: Excessive repetitive behavior is a debilitating symptom of several neuropsychiatric disorders. Parvalbumin-positive inhibitory interneurons in the dorsal striatum have been linked to repetitive behavior, and a sizable portion of these cells are surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures. Although PNNs have been associated with plasticity and neuropsychiatric disease, no previous studies have investigated their involvement in excessive repetitive behavior. Methods: We used histochemistry and confocal imaging to investigate PNNs surrounding parvalbumin-positive cells in the dorsal striatum of 4 mouse models of excessive repetitive behavior (BTBR, Cntnap2, Shank3, prenatal valproate treatment). We then investigated one of these models, the BTBR mouse, in detail, with DiI labeling, in vivo and in vitro recordings, and behavioral analyses. We next degraded PNNs in the dorsomedial striatum (DMS) using the enzyme chondroitinase ABC and assessed dendritic spine density, electrophysiology, and repetitive behavior. Results: We found a greater percentage of parvalbumin-positive interneurons with PNNs in the DMS of all 4 mouse models of excessive repetitive behavior compared with control mice. In BTBR mice, we found fewer dendritic spines on medium spiny neurons (targets of parvalbumin-positive interneurons) and differences in neuronal oscillations as well as inhibitory postsynaptic potentials compared with control mice. Reduction of DMS PNNs in BTBR mice altered dendritic spine density and inhibitory responses and normalized repetitive behavior. Conclusions: These findings suggest that cellular abnormalities in the DMS are associated with maladaptive repetitive behaviors and that manipulating PNNs can restore normal levels of repetitive behavior while altering DMS dendritic spines and inhibitory signaling.

Modular and Single-Cell Sensors of Bacterial Ser/Thr Kinase Activity.

At the single-cell level, protein kinase activity is typically inferred from downstream transcriptional reporters. However, promoters are often coregulated by several pathways, making the activity of a specific kinase difficult to deconvolve. Here, we present modular, direct, and specific sensors of bacterial kinase activity, including FRET-based sensors, as well as a synthetic transcription factor based on the lactose repressor (LacI) that has been engineered to respond to phosphorylation. We demonstrate the utility of these sensors in measuring the activity of PrkC, a conserved bacterial Ser/Thr kinase, in different growth conditions from single cells to colonies. We also show that PrkC activity increases in response to a cell-wall active antibiotic that blocks the late steps in peptidoglycan synthesis (cefotaxime), but not the early steps (fosfomycin). These sensors have a modular design that should generalize to other bacterial signaling systems in the future.

Rotational dynamics reduce interference between sensory and memory representations.

Cognition depends on integrating sensory percepts with the memory of recent stimuli. However, the distributed nature of neural coding can lead to interference between sensory and memory representations. Here, we show that the brain mitigates such interference by rotating sensory representations into orthogonal memory representations over time. To study how sensory inputs and memories are represented, we recorded neurons from the auditory cortex of mice as they implicitly learned sequences of sounds. We found that the neural population represented sensory inputs and the memory of recent stimuli in two orthogonal dimensions. The transformation of sensory information into a memory was facilitated by a combination of 'stable' neurons, which maintained their selectivity over time, and 'switching' neurons, which inverted their selectivity over time. Together, these neural responses rotated the population representation, transforming sensory inputs into memory. Theoretical modeling showed that this rotational dynamic is an efficient mechanism for generating orthogonal representations, thereby protecting memories from sensory interference.

Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture.

Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechanisms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well understood. Eligible patients (n = 80, 65 female, age: 49.3 ± 8.6 years) were enrolled and randomized into three intervention arms: (i) verum electro-acupuncture 'local' to the more affected hand; (ii) verum electro-acupuncture at 'distal' body sites, near the ankle contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles. Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5). While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in producing improvements in neurophysiological outcomes, both local to the wrist (i.e. median sensory nerve conduction latency) and in the brain (i.e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7 ± 9.9 years old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex following therapy. Our study further suggests that improvements in primary somatosensory cortex somatotopy can predict long-term clinical outcomes for carpal tunnel syndrome.

Primary somatosensory/motor cortical thickness distinguishes paresthesia-dominant from pain-dominant carpal tunnel syndrome.

Paresthesia-dominant and pain-dominant subgroups have been noted in carpal tunnel syndrome (CTS), a peripheral neuropathic disorder characterized by altered primary somatosensory/motor (S1/M1) physiology. We aimed to investigate whether brain morphometry dissociates these subgroups. Subjects with CTS were evaluated with nerve conduction studies, whereas symptom severity ratings were used to allocate subjects into paresthesia-dominant (CTS-paresthesia), pain-dominant (CTS-pain), and pain/paresthesia nondominant (not included in further analysis) subgroups. Structural brain magnetic resonance imaging data were acquired at 3T using a multiecho MPRAGE T1-weighted pulse sequence, and gray matter cortical thickness was calculated across the entire brain using validated, automated methods. CTS-paresthesia subjects demonstrated reduced median sensory nerve conduction velocity (P = 0.05) compared with CTS-pain subjects. In addition, cortical thickness in precentral and postcentral gyri (S1/M1 hand area) contralateral to the more affected hand was significantly reduced in CTS-paresthesia subgroup compared with CTS-pain subgroup. Moreover, in CTS-paresthesia subjects, precentral cortical thickness was negatively correlated with paresthesia severity (r(34) = -0.40, P = 0.016) and positively correlated with median nerve sensory velocity (r(36) = 0.51, P = 0.001), but not with pain severity. Conversely, in CTS-pain subjects, contralesional S1 (r(9) = 0.62, P = 0.042) and M1 (r(9) = 0.61, P = 0.046) cortical thickness were correlated with pain severity, but not median nerve velocity or paresthesia severity. This double dissociation in somatotopically specific S1/M1 areas suggests a neuroanatomical substrate for symptom-based CTS subgroups. Such fine-grained subgrouping of CTS may lead to improved personalized therapeutic approaches, based on superior characterization of the linkage between peripheral and central neuroplasticity.

Functional deficits in carpal tunnel syndrome reflect reorganization of primary somatosensory cortex.

Carpal tunnel syndrome, a median nerve entrapment neuropathy, is characterized by sensorimotor deficits. Recent reports have shown that this syndrome is also characterized by functional and structural neuroplasticity in the primary somatosensory cortex of the brain. However, the linkage between this neuroplasticity and the functional deficits in carpal tunnel syndrome is unknown. Sixty-three subjects with carpal tunnel syndrome aged 20-60 years and 28 age- and sex-matched healthy control subjects were evaluated with event-related functional magnetic resonance imaging at 3 T while vibrotactile stimulation was delivered to median nerve innervated (second and third) and ulnar nerve innervated (fifth) digits. For each subject, the interdigit cortical separation distance for each digit's contralateral primary somatosensory cortex representation was assessed. We also evaluated fine motor skill performance using a previously validated psychomotor performance test (maximum voluntary contraction and visuomotor pinch/release testing) and tactile discrimination capacity using a four-finger forced choice response test. These biobehavioural and clinical metrics were evaluated and correlated with the second/third interdigit cortical separation distance. Compared with healthy control subjects, subjects with carpal tunnel syndrome demonstrated reduced second/third interdigit cortical separation distance (P < 0.05) in contralateral primary somatosensory cortex, corroborating our previous preliminary multi-modal neuroimaging findings. For psychomotor performance testing, subjects with carpal tunnel syndrome demonstrated reduced maximum voluntary contraction pinch strength (P < 0.01) and a reduced number of pinch/release cycles per second (P < 0.05). Additionally, for four-finger forced-choice testing, subjects with carpal tunnel syndrome demonstrated greater response time (P < 0.05), and reduced sensory discrimination accuracy (P < 0.001) for median nerve, but not ulnar nerve, innervated digits. Moreover, the second/third interdigit cortical separation distance was negatively correlated with paraesthesia severity (r = -0.31, P < 0.05), and number of pinch/release cycles (r = -0.31, P < 0.05), and positively correlated with the second and third digit sensory discrimination accuracy (r = 0.50, P < 0.05). Therefore, reduced second/third interdigit cortical separation distance in contralateral primary somatosensory cortex was associated with worse symptomatology (particularly paraesthesia), reduced fine motor skill performance, and worse sensory discrimination accuracy for median nerve innervated digits. In conclusion, primary somatosensory cortex neuroplasticity for median nerve innervated digits in carpal tunnel syndrome is indeed maladaptive and underlies the functional deficits seen in these patients.

Frequency-dependent relationship between resting-state functional magnetic resonance imaging signal power and head motion is localized within distributed association networks.

Recent studies have highlighted the importance of analyzing spectral power in resting-state functional magnetic resonance imaging (rs-fMRI) data. Significant modulation of power has been ascribed to the performance of cognitive tasks and has been ascribed clinical significance. However, the role of confounding factors such as head motion on spectral power is not fully understood. Specifically, the spatial distribution of frequency-dependent associations between rs-fMRI power and motion is unknown. We utilized a large rs-fMRI dataset (n=1000) to quantify the influence of head motion on spectral power in different frequency bands. We (1) performed regression analyses across the entire sample and (2) computed difference maps between high- and low-motion groups, more consistent with common experimental designs, and both analyses gave similar results. Greater head motion led to reduced spectral power at lower frequencies (0.007-0.05 Hz), but increased power at higher frequencies (0.12-0.167 Hz). Importantly, our whole-brain voxel-wise analysis showed that brain areas in distributed association networks (e.g., default mode and frontoparietal control networks) were most susceptible to head motion. These results were consistent with or without global signal regression (GSR). Additionally, without GSR, we noted a positive correlation with low-frequency power in the pre- and postcentral gyrus (S1/M1), mid-cingulate cortex, and insula and a negative correlation with mid-frequency (0.05-0.12 Hz) power in S1/M1, visual, and lateral temporal cortices. Hence, head motion significantly affects rs-fMRI power and great care must be taken when assigning a diagnostic marker for clinical populations known to present with greater head motion.

Acupuncture-evoked response in somatosensory and prefrontal cortices predicts immediate pain reduction in carpal tunnel syndrome.

The linkage between brain response to acupuncture and subsequent analgesia remains poorly understood. Our aim was to evaluate this linkage in chronic pain patients with carpal tunnel syndrome (CTS). Brain response to electroacupuncture (EA) was evaluated with functional MRI. Subjects were randomized to 3 groups: (1) EA applied at local acupoints on the affected wrist (PC-7 to TW-5), (2) EA at distal acupoints (contralateral ankle, SP-6 to LV-4), and (3) sham EA at nonacupoint locations on the affected wrist. Symptom ratings were evaluated prior to and following the scan. Subjects in the local and distal groups reported reduced pain. Verum EA produced greater reduction of paresthesia compared to sham. Compared to sham EA, local EA produced greater activation in insula and S2 and greater deactivation in ipsilateral S1, while distal EA produced greater activation in S2 and deactivation in posterior cingulate cortex. Brain response to distal EA in prefrontal cortex (PFC) and brain response to verum EA in S1, SMA, and PFC were correlated with pain reduction following stimulation. Thus, while greater activation to verum acupuncture in these regions may predict subsequent analgesia, PFC activation may specifically mediate reduced pain when stimulating distal acupoints.

Acupuncture Evoked Response in Contralateral Somatosensory Cortex Reflects Peripheral Nerve Pathology of Carpal Tunnel Syndrome.

BACKGROUND: Most neuroimaging studies exploring brain response to different acupoints have been performed in healthy adults. OBJECTIVE: The aim of this study was to compare brain responses to acupuncture at local versus distal acupoints in patients with carpal tunnel syndrome (CTS), who have chronic pain, versus healthy controls (HC) and correlate these responses with median nerve function. MATERIALS AND METHODS: Brain response to electroacupuncture (EA; 2Hz) was evaluated with event-related functional MRI (fMRI) in patients with CTS (n=37) and age-matched HC (n=30). EA was applied at acupoints local (PC 7 to TW 5) and distal (SP 6 to LV 4) to the CTS lesions. RESULTS: Brain response in both groups and acupoints included activation of the bilateral secondary somatosensory cortex (S2) and insula, and the contralesional primary somatosensory cortex (cS1). Deactivation was noted in ipsilesional primary somatosensory cortex (S1). A significant difference between local and distal acupoints was found in cS1 for HC, but not CTS. Furthermore, cS1 activation by EA at local acupoints was negatively correlated with median nerve peak sensory latency in HC, but was positively correlated in CTS. No correlation was found for EA at distal acupoints for either group. CONCLUSIONS: Brain response to EA differs between CTS and HC and, for local acupoint stimulation, is associated with median nerve function, reflecting the peripheral nerve pathophysiology of CTS.