A roadmap for implanting microelectrode arrays to evoke tactile sensations through intracortical microstimulation.

Intracortical microstimulation (ICMS) is a method for restoring sensation to people with paralysis as part of a bidirectional brain-computer interface to restore upper limb function. Evoking tactile sensations of the hand through ICMS requires precise targeting of implanted electrodes. Here we describe the presurgical imaging procedures used to generate functional maps of the hand area of the somatosensory cortex and subsequent planning that guided the implantation of intracortical microelectrode arrays. In five participants with cervical spinal cord injury, across two study locations, this procedure successfully enabled ICMS-evoked sensations localized to at least the first four digits of the hand. The imaging and planning procedures developed through this clinical trial provide a roadmap for other brain-computer interface studies to ensure successful placement of stimulation electrodes.

Processing of auditory feedback in perisylvian and insular cortex.

When we speak, we not only make movements with our mouth, lips, and tongue, but we also hear the sound of our own voice. Thus, speech production in the brain involves not only controlling the movements we make, but also auditory and sensory feedback. Auditory responses are typically suppressed during speech production compared to perception, but how this manifests across space and time is unclear. Here we recorded intracranial EEG in seventeen pediatric, adolescent, and adult patients with medication-resistant epilepsy who performed a reading/listening task to investigate how other auditory responses are modulated during speech production. We identified onset and sustained responses to speech in bilateral auditory cortex, with a selective suppression of onset responses during speech production. Onset responses provide a temporal landmark during speech perception that is redundant with forward prediction during speech production. Phonological feature tuning in these "onset suppression" electrodes remained stable between perception and production. Notably, the posterior insula responded at sentence onset for both perception and production, suggesting a role in multisensory integration during feedback control.

Learning leaves a memory trace in motor cortex.

How are we able to learn new behaviors without disrupting previously learned ones? To understand how the brain achieves this, we used a brain-computer interface (BCI) learning paradigm, which enables us to detect the presence of a memory of one behavior while performing another. We found that learning to use a new BCI map altered the neural activity that monkeys produced when they returned to using a familiar BCI map in a way that was specific to the learning experience. That is, learning left a "memory trace" in the primary motor cortex. This memory trace coexisted with proficient performance under the familiar map, primarily by altering neural activity in dimensions that did not impact behavior. Forming memory traces might be how the brain is able to provide for the joint learning of multiple behaviors without interference.

Anterior versus Posterior Ventricular Catheter Placement in Pediatric Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Ventriculoperitoneal shunt placement is the mainstay of treatment for hydrocephalus, but there are relatively high rates of malfunction. Shunt catheter entry can be performed anteriorly or posteriorly, with the body of evidence from randomized controlled trials and retrospective studies suggesting conflicting findings. METHODS: A systematic review of PubMed, Medline, Scopus, and Web of Science was performed adherent to PRISMA guidelines, searching for clinical studies examining outcomes for anterior or frontal and posterior or occipital ventriculoperitoneal shunt placement. A random-effects model meta-analysis was performed on R. RESULTS: Six studies (2 randomized controlled trials and 4 retrospective cohort studies) comprising 1808 patients were identified. There were no statistically significant differences between anterior and posterior ventriculoperitoneal shunt placement for the outcomes of poor catheter placement (odds ratio [OR], 0.74; P = 0.6) and shunt infections (OR, 1.01; P = 0.9). Posterior shunts trended toward greater number of shunt revisions (OR, 0.72; P = 0.06). Six and 12 months shunt survival was comparable between anterior and posterior approaches (P > 0.05). There were significant differences between long-term shunt survival (2 and 5 years shunt survival), favoring anterior shunt placement with greater odds of survival (OR, 1.91 and OR, 1.62, respectively; P < 0.05). CONCLUSIONS: We show that although anteriorly and posteriorly placed shunts have mostly comparable outcomes, shunt survival at 2-year and 5-year intervals favors anteriorly placed shunts. Additional well-designed clinical trials are needed to validate the findings of greater late shunt failure in posteriorly placed shunts, with more time-dependent statistical measures.

Reproducibility of graph measures derived from resting-state MEG functional connectivity metrics in sensor and source spaces.

Prior studies have used graph analysis of resting-state magnetoencephalography (MEG) to characterize abnormal brain networks in neurological disorders. However, a present challenge for researchers is the lack of guidance on which network construction strategies to employ. The reproducibility of graph measures is important for their use as clinical biomarkers. Furthermore, global graph measures should ideally not depend on whether the analysis was performed in the sensor or source space. Therefore, MEG data of the 89 healthy subjects of the Human Connectome Project were used to investigate test-retest reliability and sensor versus source association of global graph measures. Atlas-based beamforming was used for source reconstruction, and functional connectivity (FC) was estimated for both sensor and source signals in six frequency bands using the debiased weighted phase lag index (dwPLI), amplitude envelope correlation (AEC), and leakage-corrected AEC. Reliability was examined over multiple network density levels achieved with proportional weight and orthogonal minimum spanning tree thresholding. At a 100% density, graph measures for most FC metrics and frequency bands had fair to excellent reliability and significant sensor versus source association. The greatest reliability and sensor versus source association was obtained when using amplitude metrics. Reliability was similar between sensor and source spaces when using amplitude metrics but greater for the source than the sensor space in higher frequency bands when using the dwPLI. These results suggest that graph measures are useful biomarkers, particularly for investigating functional networks based on amplitude synchrony.

Explant Analysis of Utah Electrode Arrays Implanted in Human Cortex for Brain-Computer-Interfaces.

Brain-computer interfaces are being developed to restore movement for people living with paralysis due to injury or disease. Although the therapeutic potential is great, long-term stability of the interface is critical for widespread clinical implementation. While many factors can affect recording and stimulation performance including electrode material stability and host tissue reaction, these factors have not been investigated in human implants. In this clinical study, we sought to characterize the material integrity and biological tissue encapsulation via explant analysis in an effort to identify factors that influence electrophysiological performance. We examined a total of six Utah arrays explanted from two human participants involved in intracortical BCI studies. Two platinum (Pt) arrays were implanted for 980 days in one participant (P1) and two Pt and two iridium oxide (IrOx) arrays were implanted for 182 days in the second participant (P2). We observed that the recording quality followed a similar trend in all six arrays with an initial increase in peak-to-peak voltage during the first 30-40 days and gradual decline thereafter in P1. Using optical and two-photon microscopy we observed a higher degree of tissue encapsulation on both arrays implanted for longer durations in participant P1. We then used scanning electron microscopy and energy dispersive X-ray spectroscopy to assess material degradation. All measures of material degradation for the Pt arrays were found to be more prominent in the participant with a longer implantation time. Two IrOx arrays were subjected to brief survey stimulations, and one of these arrays showed loss of iridium from most of the stimulated sites. Recording performance appeared to be unaffected by this loss of iridium, suggesting that the adhesion of IrOx coating may have been compromised by the stimulation, but the metal layer did not detach until or after array removal. In summary, both tissue encapsulation and material degradation were more pronounced in the arrays that were implanted for a longer duration. Additionally, these arrays also had lower signal amplitude and impedance. New biomaterial strategies that minimize fibrotic encapsulation and enhance material stability should be developed to achieve high quality recording and stimulation for longer implantation periods.

Replacing Computed Tomography with "Rapid" Magnetic Resonance Imaging for Ventricular Shunt Imaging.

INTRODUCTION: Children with ventricular shunts undergo frequent neuroimaging, and therefore, radiation exposures, to evaluate shunt malfunctions. The objective of this study was to safely reduce radiation exposure in this population by reducing computed tomography (CT) and increasing "rapid" magnetic resonance imaging (rMRI-shunt) among patients warranting neuroimaging for possible shunt malfunction. METHODS: This was a single-center quality improvement study in a tertiary care pediatric emergency department (ED). We implemented a multidisciplinary guideline for ED shunt evaluation, which promoted the use of rMRI-shunt over CT. We included patients younger than 18 years undergoing an ED shunt evaluation during 11 months of the preintervention and 25 months of the intervention study periods. The primary outcome was the CT rate, and we evaluated the relevant process and balancing measures. RESULTS: There were 266 encounters preintervention and 488 during the intervention periods with similar neuroimaging rates (80.7% versus 81.5%, P = 0.8.) CT decreased from 90.1% to 34.8% (difference -55.3%, 95% confidence interval [CI]: -71.1, -25.8), and rMRI-shunt increased from 9.9% to 65.2% (difference 55.3%, 95% CI: 25.8, 71.1) during the preintervention and intervention periods, respectively. There were increases in the mean time to neuroimaging (53.1 min; [95% CI: 41.6, 64.6]) and ED length of stay (LOS) (52.3 min; [95% CI: 36.8, 67.6]), without changes in total neuroimaging, 72-hour revisits, or follow-up neuroimaging. CONCLUSIONS: Multidisciplinary implementation of a standardized guideline reduced CT and increased rMRI-shunt use in a pediatric ED setting. Clinicians should balance the reduction in radiation exposure with ED rMRI-shunt for patients with ventricular shunts against the increased time of obtaining imaging and LOS.

A brain-computer interface that evokes tactile sensations improves robotic arm control.

Prosthetic arms controlled by a brain-computer interface can enable people with tetraplegia to perform functional movements. However, vision provides limited feedback because information about grasping objects is best relayed through tactile feedback. We supplemented vision with tactile percepts evoked using a bidirectional brain-computer interface that records neural activity from the motor cortex and generates tactile sensations through intracortical microstimulation of the somatosensory cortex. This enabled a person with tetraplegia to substantially improve performance with a robotic limb; trial times on a clinical upper-limb assessment were reduced by half, from a median time of 20.9 to 10.2 seconds. Faster times were primarily due to less time spent attempting to grasp objects, revealing that mimicking known biological control principles results in task performance that is closer to able-bodied human abilities.

MRI-guided laser interstitial thermal therapy using the Visualase system and Navigus frameless stereotaxy in an infant: technical case report.

Laser interstitial thermal therapy (LITT) is increasingly used as a surgical option for the treatment of epilepsy. Placement of the laser fibers relies on stereotactic navigation with cranial fixation pins. In addition, the laser fiber is stabilized in the cranium during the ablation using a cranial bolt that assumes maturity of the skull. Therefore, younger infants (< 2 years of age) have traditionally not been considered as candidates for LITT. However, LITT is an appealing option for patients with familial epilepsy syndromes, such as tuberous sclerosis complex (TSC), due to the multiplicity of lesions and the likely need for multiple procedures. A 4-month-old infant with TSC presented with refractory focal seizures despite receiving escalating doses of 5 antiepileptic medications. Electrographic and clinical seizures occurred numerous times daily. Noninvasive evaluations, including MRI, magnetoencephalography, scalp EEG, and SPECT, localized the ictal onset to a left frontal cortical tuber in the premotor area. In this paper, the authors report a novel technique to overcome the challenges of performing LITT in an infant with an immature skull by repurposing the Navigus biopsy skull mount for stereotactic placement of a laser fiber using electromagnetic-based navigation. The patient underwent successful ablation of the tuber and remained seizure free 4 months postoperatively. To the authors' knowledge, this is the youngest reported patient to undergo LITT. A safe method is described to perform LITT in an infant using commonly available tools without dedicated instrumentation beyond standard stereotactic navigation, a biopsy platform, and the Visualase system.

Learning is shaped by abrupt changes in neural engagement.

Internal states such as arousal, attention and motivation modulate brain-wide neural activity, but how these processes interact with learning is not well understood. During learning, the brain modifies its neural activity to improve behavior. How do internal states affect this process? Using a brain-computer interface learning paradigm in monkeys, we identified large, abrupt fluctuations in neural population activity in motor cortex indicative of arousal-like internal state changes, which we term 'neural engagement.' In a brain-computer interface, the causal relationship between neural activity and behavior is known, allowing us to understand how neural engagement impacted behavioral performance for different task goals. We observed stereotyped changes in neural engagement that occurred regardless of how they impacted performance. This allowed us to predict how quickly different task goals were learned. These results suggest that changes in internal states, even those seemingly unrelated to goal-seeking behavior, can systematically influence how behavior improves with learning.

Long-term outcomes in the treatment of pediatric skull base chordomas in the endoscopic endonasal era.

OBJECTIVE: Pediatric skull base chordoma is a rare entity that is traditionally considered to display aggressive behavior with an increased risk of recurrence. There is an absence of literature examining outcomes in the pediatric population in general and using the endoscopic endonasal approach (EEA). METHODS: The authors retrospectively reviewed all patients with skull base chordomas presenting by the age of 18 years to the Children's Hospital of Pittsburgh or the University of Pittsburgh Medical Center from 2004 to 2019. Clinical outcomes, the number and location of recurrences, and progression-free survival time were determined. RESULTS: Twenty patients met the study criteria. The most common presenting complaints were diplopia (n = 7), headache (n = 6), and swallowing difficulty (n = 4). Three cases were incidentally discovered. Twelve patients underwent single-stage EEA alone, 2 patients had two-stage EEA, and 6 patients had combined EEA with open far-lateral or extreme-lateral approaches. Fourteen patients underwent gross-total resection (GTR), and 6 patients had near-total resection. Larger tumors were more likely to require staging or a combined approach (86% vs 7%) and were less likely to receive GTR (33% vs 86%) but had comparable recurrence and mortality rates. Five patients developed CSF leaks requiring reoperation, 2 patients developed a permanent abducens nerve palsy, 1 patient suffered an internal carotid artery injury, 1 patient developed an epidural hematoma, and 1 patient developed a subdural empyema. Four (20%) patients had recurrence during follow-up (mean radiographic follow-up 59 months and mean time to local recurrence 19 months). Two patients with recurrence underwent further resection, and 1 patient elected to stop treatment. Both patients who underwent repeat resection experienced a second recurrence, one of whom elected to stop treatment. Both patients who died had an elevated Ki-67 (p = 0.039), one of whom developed de-differentiated histology. A third patient died of progressive spinal metastases without local recurrence and is one of 2 patients who developed postoperative spinal metastases. Both patients whose tumors became de-differentiated progressed from tumors with an initial Ki-67 of 15 or greater (p = 0.035) and received prior radiotherapy to the bulk tumor (p = 0.03). CONCLUSIONS: The majority of pediatric skull base chordomas, when managed at a specialized center with a goal of GTR, may have a better outcome than traditionally believed. Elevated Ki-67 rates may predict poor outcome and progression to de-differentiation.

Endoscopic Endonasal Approach for Craniopharyngiomas with Intraventricular Extension: Case Series, Long-Term Outcomes, and Review.

BACKGROUND: Traditionally, craniopharyngiomas with intraventricular extension were approached transcranially; however, endoscopic approaches are now increasingly used. We sought to study the endoscopic endonasal approach (EEA) in the setting of complex craniopharyngiomas with intraventricular extension and to compare it with existing literature. METHODS: Patients undergoing EEA for resection of craniopharyngioma with ventricular involvement from 2002 to 2015 were retrospectively reviewed. Outcomes were compared with previously published EEA and transcranial approach (TCA) studies for all craniopharyngioma locations. RESULTS: Sixty-two patients were included. Average tumor and intraventricular volume were 13.93 cm3 and 2.61 cm3, respectively. Patients presented with visual impairment, endocrinopathy, and, headache. Gross total resection (GTR) was achieved in 47% of all cases and increased to 77% after 2012 Approximately 98% experienced improvement or stability of vision. Postoperative cerebrospinal fluid (CSF) leak and meningitis rates were 19% and 8.1%, respectively. However, nasoseptal flap (NSF) use reduced CSF leak rate to 10%. Six (9.6%) patients required shunting before resection and 25% were shunted postoperatively. Seven of 10 patients (70%) treated before NSF use required shunting, whereas only 7 of 46 (15%) required shunting with NSF reconstruction. Review demonstrated similar outcomes between the present cohort and EEA or TCA for all craniopharyngioma locations. TCA had a greater GTR, however, with large study variation. EEA showed improved visual outcomes but also increased CSF leaks. CONCLUSIONS: EEA for craniopharyngiomas with intraventricular extension shows similar outcomes to TCA and EEA for all craniopharyngiomas, expanding this anatomic limit. Given ventricular involvement, CSF leak rates are expectedly high. GTR increased and CSF leak rates dramatically decreased with time, suggestive of the steep learning curve to complex resection.

Stabilization of a brain-computer interface via the alignment of low-dimensional spaces of neural activity.

The instability of neural recordings can render clinical brain-computer interfaces (BCIs) uncontrollable. Here, we show that the alignment of low-dimensional neural manifolds (low-dimensional spaces that describe specific correlation patterns between neurons) can be used to stabilize neural activity, thereby maintaining BCI performance in the presence of recording instabilities. We evaluated the stabilizer with non-human primates during online cursor control via intracortical BCIs in the presence of severe and abrupt recording instabilities. The stabilized BCIs recovered proficient control under different instability conditions and across multiple days. The stabilizer does not require knowledge of user intent and can outperform supervised recalibration. It stabilized BCIs even when neural activity contained little information about the direction of cursor movement. The stabilizer may be applicable to other neural interfaces and may improve the clinical viability of BCIs.

Classification of Individual Finger Movements Using Intracortical Recordings in Human Motor Cortex.

BACKGROUND: Intracortical microelectrode arrays have enabled people with tetraplegia to use a brain-computer interface for reaching and grasping. In order to restore dexterous movements, it will be necessary to control individual fingers. OBJECTIVE: To predict which finger a participant with hand paralysis was attempting to move using intracortical data recorded from the motor cortex. METHODS: A 31-yr-old man with a C5/6 ASIA B spinal cord injury was implanted with 2 88-channel microelectrode arrays in left motor cortex. Across 3 d, the participant observed a virtual hand flex in each finger while neural firing rates were recorded. A 6-class linear discriminant analysis (LDA) classifier, with 10 × 10-fold cross-validation, was used to predict which finger movement was being performed (flexion/extension of all 5 digits and adduction/abduction of the thumb). RESULTS: The mean overall classification accuracy was 67% (range: 65%-76%, chance: 17%), which occurred at an average of 560 ms (range: 420-780 ms) after movement onset. Individually, thumb flexion and thumb adduction were classified with the highest accuracies at 92% and 93%, respectively. The index, middle, ring, and little achieved an accuracy of 65%, 59%, 43%, and 56%, respectively, and, when incorrectly classified, were typically marked as an adjacent finger. The classification accuracies were reflected in a low-dimensional projection of the neural data into LDA space, where the thumb-related movements were most separable from the finger movements. CONCLUSION: Classification of intention to move individual fingers was accurately predicted by intracortical recordings from a human participant with the thumb being particularly independent.

Radiological and clinical predictors of scoliosis in patients with Chiari malformation type I and spinal cord syrinx from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: Scoliosis is frequently a presenting sign of Chiari malformation type I (CM-I) with syrinx. The authors' goal was to define scoliosis in this population and describe how radiological characteristics of CM-I and syrinx relate to the presence and severity of scoliosis. METHODS: A large multicenter retrospective and prospective registry of pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for clinical and radiological characteristics of CM-I, syrinx, and scoliosis (coronal curve ≥ 10°). RESULTS: Based on available imaging of patients with CM-I and syrinx, 260 of 825 patients (31%) had a clear diagnosis of scoliosis based on radiographs or coronal MRI. Forty-nine patients (5.9%) did not have scoliosis, and in 516 (63%) patients, a clear determination of the presence or absence of scoliosis could not be made. Comparison of patients with and those without a definite scoliosis diagnosis indicated that scoliosis was associated with wider syrinxes (8.7 vs 6.3 mm, OR 1.25, p < 0.001), longer syrinxes (10.3 vs 6.2 levels, OR 1.18, p < 0.001), syrinxes with their rostral extent located in the cervical spine (94% vs 80%, OR 3.91, p = 0.001), and holocord syrinxes (50% vs 16%, OR 5.61, p < 0.001). Multivariable regression analysis revealed syrinx length and the presence of holocord syrinx to be independent predictors of scoliosis in this patient cohort. Scoliosis was not associated with sex, age at CM-I diagnosis, tonsil position, pB-C2 distance (measured perpendicular distance from the ventral dura to a line drawn from the basion to the posterior-inferior aspect of C2), clivoaxial angle, or frontal-occipital horn ratio. Average curve magnitude was 29.9°, and 37.7% of patients had a left thoracic curve. Older age at CM-I or syrinx diagnosis (p < 0.0001) was associated with greater curve magnitude whereas there was no association between syrinx dimensions and curve magnitude. CONCLUSIONS: Syrinx characteristics, but not tonsil position, were related to the presence of scoliosis in patients with CM-I, and there was an independent association of syrinx length and holocord syrinx with scoliosis. Further study is needed to evaluate the nature of the relationship between syrinx and scoliosis in patients with CM-I.

New neural activity patterns emerge with long-term learning.

Learning has been associated with changes in the brain at every level of organization. However, it remains difficult to establish a causal link between specific changes in the brain and new behavioral abilities. We establish that new neural activity patterns emerge with learning. We demonstrate that these new neural activity patterns cause the new behavior. Thus, the formation of new patterns of neural population activity can underlie the learning of new skills.

Long-term impact of pediatric endoscopic endonasal skull base surgery on midface growth.

OBJECTIVE: Cranial base development plays a large role in anterior and vertical maxillary growth through 7 years of age, and the effect of early endonasal cranial base surgery on midface growth is unknown. The authors present their experience with pediatric endoscopic endonasal surgery (EES) and long-term midface growth. METHODS: This is a retrospective review of cases where EES was performed from 2000 to 2016. Patients who underwent their first EES of the skull base before age 7 (prior to cranial suture fusion) and had a complete set of pre- and postoperative imaging studies (CT or MRI) with at least 1 year of follow-up were included. A radiologist performed measurements (sella-nasion [S-N] distance and angles between the sella, nasion, and the most concave points of the anterior maxilla [A point] or anterior mandibular synthesis [B point], the SNA, SNB, and ANB angles), which were compared to age- and sex-matched Bolton standards. A Z-score test was used; significance was set at p < 0.05. RESULTS: The early surgery group had 11 patients, with an average follow-up of 5 years; the late surgery group had 33 patients. Most tumors were benign; 1 patient with a panclival arteriovenous malformation was a significant outlier for all measurements. Comparing the measurements obtained in the early surgery group to Bolton standard norms, the authors found no significant difference in postoperative SNA (p = 0.10), SNB (p = 0.14), or ANB (0.67) angles. The S-N distance was reduced both pre- and postoperatively (SD 1.5, p = 0.01 and p = 0.009). Sex had no significant effect. Compared to patients who had surgery after the age of 7 years, the early surgery group demonstrated no significant difference in pre- to postoperative changes with regard to S-N distance (p = 0.87), SNA angle (p = 0.89), or ANB angle (p = 0.14). Lesion type (craniopharyngioma, angiofibroma, and other types) had no significant effect in either age group. CONCLUSIONS: Though our cohort of patients with skull base lesions demonstrated some abnormal measurements in the maxillary-mandibular relationship before their operation, their postoperative cephalometrics fell within the normal range and showed no significant difference from those of patients who underwent operations at an older age. Therefore, there appears to be no evidence of impact of endoscopic endonasal skull base surgery on craniofacial development within the growth period studied.

Constraints on neural redundancy.

Millions of neurons drive the activity of hundreds of muscles, meaning many different neural population activity patterns could generate the same movement. Studies have suggested that these redundant (i.e. behaviorally equivalent) activity patterns may be beneficial for neural computation. However, it is unknown what constraints may limit the selection of different redundant activity patterns. We leveraged a brain-computer interface, allowing us to define precisely which neural activity patterns were redundant. Rhesus monkeys made cursor movements by modulating neural activity in primary motor cortex. We attempted to predict the observed distribution of redundant neural activity. Principles inspired by work on muscular redundancy did not accurately predict these distributions. Surprisingly, the distributions of redundant neural activity and task-relevant activity were coupled, which enabled accurate predictions of the distributions of redundant activity. This suggests limits on the extent to which redundancy may be exploited by the brain for computation.

Publisher Correction: Learning by neural reassociation.

In the version of this article initially published, equation (10) contained cos Θ instead of sin Θ as the bottom element of the right-hand vector. The error has been corrected in the HTML and PDF versions of the article.

Learning by neural reassociation.

Behavior is driven by coordinated activity across a population of neurons. Learning requires the brain to change the neural population activity produced to achieve a given behavioral goal. How does population activity reorganize during learning? We studied intracortical population activity in the primary motor cortex of rhesus macaques during short-term learning in a brain-computer interface (BCI) task. In a BCI, the mapping between neural activity and behavior is exactly known, enabling us to rigorously define hypotheses about neural reorganization during learning. We found that changes in population activity followed a suboptimal neural strategy of reassociation: animals relied on a fixed repertoire of activity patterns and associated those patterns with different movements after learning. These results indicate that the activity patterns that a neural population can generate are even more constrained than previously thought and might explain why it is often difficult to quickly learn to a high level of proficiency.