Aging suppresses subthalamic neuronal activity in patients with Parkinson's disease.

Age is a primary risk factor for Parkinson's disease (PD); however, the effects of aging on the Parkinsonian brain remain poorly understood, particularly for deep brain structures. We investigated intraoperative micro-electrode recordings from the subthalamic nucleus (STN) of PD patients aged between 42 and 76 years. Age was associated with decreased oscillatory beta power and non-oscillatory high-frequency power, independent of PD-related variables. Single unit firing and burst rates were also reduced, whereas the coefficient of variation and the structure of burst activity were unchanged. Phase synchronization (debiased weighed phase lag index [dWPLI]) between sites was pronounced in the beta band between electrodes in the superficial STN but was unaffected by age. Our results show that aging is associated with reduced neuronal activity without changes to its temporal structure. We speculate that the loss of activity in the STN may mediate the relationship between PD and age.

Invasive neurophysiological recordings in human basal ganglia. What have we learned about non-motor behaviour?

Research into the function of deep brain structures has benefited greatly from microelectrode recordings in animals. This has helped to unravel physiological processes in the healthy and malfunctioning brain. Translation to the human is necessary for improving basic understanding of subcortical structures and their implications in diseases. The use of microelectrode recordings as a standard component of deep brain stimulation surgery offers the most viable route for studying the electrophysiology of single cells and local neuronal populations in important deep structures of the human brain. Most of the studies in the basal ganglia have targeted the motor loop and movement disorder pathophysiology. In recent years, however, research has diversified to include limbic and cognitive processes. This review aims to provide an overview of advances in neuroscience made using intraoperative and post-operative recordings with a focus on non-motor activity in the basal ganglia.

Transient susceptibility to interference at event boundaries impacts long-term memory of naturalistic episodes.

During ongoing narratives, event boundaries trigger processes relevant for subsequent memory. Previous work has shown that novel, unrelated input presented at an event boundary can retroactively interfere with short-term retention of the preceding event. This interference was attributed to a perturbation of offset-related processes taking place within seconds after encoding and supporting the binding of elements into a coherent event memory. However, the temporal specificity of this memory interference and whether its impact extends to longer retention delays has not been addressed. Here, participants viewed either individual or pairs of short narrative movie clips. Susceptibility to interference at event boundaries was probed by presenting the second clip either immediately after the first, or with a 2s encoding delay. In free and cued recall, after 20 min and 24 h, only memory for movie clips that were immediately followed by a second clip was reduced compared to clips shown in isolation. Intact offset-related processes (as indexed by successful recall of the first movie) did not negatively affect encoding of the subsequent clip. Together, these results indicate that the 2s time-window immediately after an event is relevant for successful consolidation and long-term retention of memory.

Inconsistencies in atlas-based volumetric measures of the human nucleus basalis of Meynert: A need for high-resolution alternatives.

The nucleus basalis of Meynert (nbM) is the major source of cortical acetylcholine (ACh) and has been related to cognitive processes and to neurological disorders. However, spatially delineating the human nbM in MRI studies remains challenging. Due to the absence of a functional localiser for the human nbM, studies to date have localised it using nearby neuroanatomical landmarks or using probabilistic atlases. To understand the feasibility of MRI of the nbM we set our four goals; our first goal was to review current human nbM region-of-interest (ROI) selection protocols used in MRI studies, which we found have reported highly variable nbM volume estimates. Our next goal was to quantify and discuss the limitations of existing atlas-based volumetry of nbM. We found that the identified ROI volume depends heavily on the atlas used and on the probabilistic threshold set. In addition, we found large disparities even for data/studies using the same atlas and threshold. To test whether spatial resolution contributes to volume variability, as our third goal, we developed a novel nbM mask based on the normalized BigBrain dataset. We found that as long as the spatial resolution of the target data was 1.3 mm isotropic or above, our novel nbM mask offered realistic and stable volume estimates. Finally, as our last goal we tried to discern nbM using publicly available and novel high resolution structural MRI ex vivo MRI datasets. We find that, using an optimised 9.4T quantitative T2⁎ ex vivo dataset, the nbM can be visualised using MRI. We conclude caution is needed when applying the current methods of mapping nbM, especially for high resolution MRI data. Direct imaging of the nbM appears feasible and would eliminate the problems we identify, although further development is required to allow such imaging using standard (f)MRI scanning.

Spatiotemporal patterns of sleep spindle activity in human anterior thalamus and cortex.

Sleep spindles (8 - 16 Hz) are transient electrophysiological events during non-rapid eye movement sleep. While sleep spindles are routinely observed in the cortex using scalp electroencephalography (EEG), recordings of their thalamic counterparts have not been widely studied in humans. Based on a few existing studies, it has been hypothesized that spindles occur as largely local phenomena. We investigated intra-thalamic and thalamocortical spindle co-occurrence, which may underlie thalamocortical communication. We obtained scalp EEG and thalamic recordings from 7 patients that received bilateral deep brain stimulation (DBS) electrodes to the anterior thalamus for the treatment of drug resistant focal epilepsy. Spindles were categorized into subtypes based on their main frequency (i.e., slow (10±2 Hz) or fast (14±2 Hz)) and their level of thalamic involvement (spanning one channel, or spreading uni- or bilaterally within the thalamus). For the first time, we contrasted observed spindle patterns with permuted data to estimate random spindle co-occurrence. We found that multichannel spindle patterns were systematically coordinated at the thalamic and thalamocortical level. Importantly, distinct topographical patterns of thalamocortical spindle overlap were associated with slow and fast subtypes of spindles. These observations provide further evidence for coordinated spindle activity in thalamocortical networks.

Empirically constrained network models for contrast-dependent modulation of gamma rhythm in V1.

Gamma oscillations are thought to play a key role in neuronal network function and neuronal communication, yet the underlying generating mechanisms have not been fully elucidated to date. At least partly, this may be due to the fact that even in simple network models of interconnected inhibitory (I) and excitatory (E) neurons, many parameters remain unknown and are set based on practical considerations or by convention. Here, we mitigate this problem by requiring PING (Pyramidal Interneuron Network Gamma) models to simultaneously satisfy a broad set of criteria for realistic behaviour based on empirical data spanning both the single unit (spikes) and local population (LFP) levels while unknown parameters are varied. By doing so, we were able to constrain the parameter ranges and select empirically valid models. The derived model constraints implied weak rather than strong PING as the generating mechanism for gamma, connectivity between E and I neurons within specific bounds, and variations of the external input to E but not I neurons. Constrained models showed valid behaviours, including gamma frequency increases with contrast and power saturation or decay at high contrasts. Using an empirically-validated model we studied the route to gamma instability at high contrasts. This involved increased heterogeneity of E neurons with increasing input triggering a breakdown of I neuron pacemaker function. Further, we illustrate the model's capacity to resolve disputes in the literature concerning gamma oscillation properties and GABA conductance proxies. We propose that the models derived in our study will be useful for other modelling studies, and that our approach to the empirical constraining of PING models can be expanded when richer empirical datasets become available. As local gamma networks are the building blocks of larger networks that aim to understand complex cognition through their interactions, there is considerable value in improving our models of these building blocks.

Noise-induced neurophysiological alterations in the rat medial geniculate body and thalamocortical desynchronization by deep brain stimulation.

The thalamic medial geniculate body (MGB) is uniquely positioned within the neural tinnitus networks. Deep brain stimulation (DBS) of the MGB has been proposed as a possible novel treatment for tinnitus, yet mechanisms remain elusive. The aim of this study was to characterize neurophysiologic hallmarks in the MGB after noise exposure and to assess the neurophysiological effects of electrical stimulation of the MGB. Fourteen male Sprague-Dawley rats were included. Nine subjects were unilaterally exposed to a 16-kHz octave-band noise at 115 dB for 90 min, five received sham exposure. Single units were recorded from the contralateral MGB where spontaneous firing, coefficient of variation, response type, rate-level functions, and thresholds were determined. Local field potentials and electroencephalographical (EEG) recordings were performed before and after high-frequency DBS of the MGB. Thalamocortical synchronization and power were analyzed. In total, 214 single units were identified (n = 145 in noise-exposed group, n = 69 in control group). After noise exposure, fast-responding neurons become less responsive or nonresponsive without change to their spontaneous rate, whereas sustained- and suppressed-type neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activity. MGB DBS suppressed thalamocortical synchronization in the ß and γ bands, supporting suppression of thalamocortical synchronization as an underlying mechanism of tinnitus suppression by high frequency DBS. These findings contribute to our understanding of the neurophysiologic consequences of noise exposure and the mechanism of potential DBS therapy for tinnitus.NEW & NOTEWORTHY Separate functional classes of MGB neurons might have distinct roles in tinnitus pathophysiology. After noise exposure, fast-responding neurons become less responsive or nonresponsive without change to their spontaneous firing, whereas sustained and suppressed neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activity. Furthermore, results suggest desynchronization of thalamocortical ß and γ oscillations as a mechanism of tinnitus suppression by MGB DBS.

Microsaccade-rhythmic modulation of neural synchronization and coding within and across cortical areas V1 and V2.

Primates sample their visual environment actively through saccades and microsaccades (MSs). Saccadic eye movements not only modulate neural spike rates but might also affect temporal correlations (synchrony) among neurons. Neural synchrony plays a role in neural coding and modulates information transfer between cortical areas. The question arises of how eye movements shape neural synchrony within and across cortical areas and how it affects visual processing. Through local field recordings in macaque early visual cortex while monitoring eye position and through neural network simulations, we find 2 distinct synchrony regimes in early visual cortex that are embedded in a 3- to 4-Hz MS-related rhythm during visual fixation. In the period shortly after an MS ("transient period"), synchrony was high within and between cortical areas. In the subsequent period ("sustained period"), overall synchrony dropped and became selective to stimulus properties. Only mutually connected neurons with similar stimulus responses exhibited sustained narrow-band gamma synchrony (25-80 Hz), both within and across cortical areas. Recordings in macaque V1 and V2 matched the model predictions. Furthermore, our modeling provides predictions on how (micro)saccade-modulated gamma synchrony in V1 shapes V2 receptive fields (RFs). We suggest that the rhythmic alternation between synchronization regimes represents a basic repeating sampling strategy of the visual system.

The Attentional Blink is Related to the Microsaccade Rate Signature.

The reduced detectability of a target T2 following discrimination of a preceding target T1 in the attentional blink (AB) paradigm is classically interpreted as a consequence of reduced attention to T2 due to attentional allocation to T1. Here, we investigated whether AB was related to changes in microsaccade rate (MSR). We found a pronounced MSR signature following T1 onset, characterized by MSR suppression from 200 to 328 ms and enhancement from 380 to 568 ms. Across participants, the magnitude of the MSR suppression correlated with the AB effect such that low T2 detectability corresponded to reduced MSR. However, in the same task, T1 error trials coincided with the presence of microsaccades. We discuss this apparent paradox in terms of known neurophysiological correlates of MS whereby cortical excitability is suppressed both during the microsaccade and MSR suppression, in accordance to poor T1 performance with microsaccade occurrence and poor T2 performance with microsaccade absence. Our data suggest a novel low-level mechanism contributing to AB characterized by reduced MSR, thought to cause suppressed visual cortex excitability. This opens the question of whether attention mediates T2 performance suppression independently from MSR, and if not, how attention interacts with MSR to produce the T2 performance suppression.

Diminished Alpha Lateralization During Working Memory but Not During Attentional Cueing in Older Adults.

Aging has been associated with declined performance in tasks that rely on working memory (WM). Because attention and WM are tightly coupled, declined performance on a WM task in older adults could be due to deficits in attention, memory capacity, or both. We used alpha (8-14 Hz) power modulations as an index to assess how changes in attention and memory capacity contribute to decreased WM performance in older adults. We recorded the magnetoencephalogram in healthy older (60-76 years) and younger adults (18-28 years) while they performed a lateralized WM task. At matched difficulty, older adults showed significantly lower memory spans than younger adults. Alpha lateralization during retention was nearly absent in older adults due to a bilateral reduction of alpha power. By contrast, in younger adults alpha power was reduced only contralateral to the attended hemifield. Surprisingly, during the cue interval, both groups showed equal alpha lateralization. The preserved alpha lateralization during attentional cueing, and lack thereof during retention, suggests that reduced WM performance in older adults is due to deficits in WM-related processes, not deficits in attentional orienting, and that a compensatory mechanism in aging permits significant residual WM performance in the absence of alpha lateralization.

Effect of Anesthesia on Microelectrode Recordings during Deep Brain Stimulation Surgery in Tourette Syndrome Patients.

BACKGROUND: Deep brain stimulation (DBS) is an accepted treatment for patients with medication-resistant Tourette syndrome (TS). Sedation is commonly required during electrode implantation to attenuate anxiety, pain, and severe tics. Anesthetic agents potentially impair the quality of microelectrode recordings (MER). Little is known about the effect of these anesthetics on MER in patients with TS. We describe our experience with different sedative regimens on MER and tic severity in patients with TS. METHODS: The clinical records of all TS patients who underwent DBS surgery between 2010 and 2018 were reviewed. Demographic data, stimulation targets, anesthetic agents, perioperative complications, and MER from each hemisphere were collected and analyzed. Single-unit activity was identified by filtering spiking activity from broadband MER data and principal component analysis with K-means clustering. Vocal and motor tics which caused artifacts in the MER data were manually selected using visual and auditory inspection. RESULTS: Six patients underwent bilateral DBS electrode implantation. In all patients, the target was the anterior internal globus pallidus. Patient comfort and hemodynamic and respiratory stability were maintained with conscious sedation with one or more of the following anesthetic drugs: propofol, midazolam, remifentanil, clonidine, and dexmedetomidine. Good quality MER and clinical testing were obtained in 9 hemispheres of 6 patients. In 3 patients, MER quality was poor on one side. CONCLUSION: Cautiously applied sedative drugs can provide patient comfort, hemodynamic and respiratory stability, and suppress severe tics, with minimal interference with MER.

Behavioural interference at event boundaries reduces long-term memory performance in the virtual water maze task without affecting working memory performance.

Narrative episodic memory of movie clips can be retroactively impaired by presenting unrelated stimuli coinciding with event boundaries. This effect has been linked with rapid hippocampal processes triggered by the offset of the event, that are alternatively related either to memory consolidation or with working memory processes. Here we tested whether this effect extended to spatial memory, the temporal specificity and extent of the interference, and its effect on working- vs long-term memory. In three computerized adaptations of the Morris Water Maze, participants learned the location of an invisible target over three trials each. A second spatial navigation task was presented either immediately after finding the target, after a 10-s delay, or no second task was presented (control condition). A recall session, in which participants indicated the learned target location with 10 'pin-drop' trials for each condition, was performed after a 1-h or a 24-h break. Spatial memory was measured by the mean distance between pins and the true location. Results indicated that the immediate presentation of the second task led to worse memory performance, for both break durations, compared to the delayed condition. There was no difference in performance between the delayed presentation and the control condition. Despite this long-term memory effect, we found no difference in the rate of performance improvement during the learning session, indicating no effect of the second task on working memory. Our findings are in line with a rapid process, linked to the offset of an event, that is involved in the early stages of memory consolidation.

Dorsal subthalamic nucleus targeting in deep brain stimulation: microelectrode recording versus 7-Tesla connectivity.

Connectivity-derived 7-Tesla MRI segmentation and intraoperative microelectrode recording can both assist subthalamic nucleus targeting for deep brain stimulation in Parkinson's disease. It remains unclear whether deep brain stimulation electrodes placed in the 7-Tesla MRI segmented subdivision with predominant projections to cortical motor areas (hyperdirect pathway) achieve superior motor improvement and whether microelectrode recording can accurately distinguish the motor subdivision. In 25 patients with Parkinson's disease, deep brain stimulation electrodes were evaluated for being inside or outside the predominantly motor-connected subthalamic nucleus (motor-connected subthalamic nucleus or non-motor-connected subthalamic nucleus, respectively) based on 7-Tesla MRI connectivity segmentation. Hemi-body motor improvement (Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III) and microelectrode recording characteristics of multi- and single-unit activities were compared between groups. Deep brain stimulation electrodes placed in the motor-connected subthalamic nucleus resulted in higher hemi-body motor improvement, compared with electrodes placed in the non-motor-connected subthalamic nucleus (80% versus 52%, P < 0.0001). Multi-unit activity was found slightly higher in the motor-connected subthalamic nucleus versus the non-motor-connected subthalamic nucleus (P < 0.001, receiver operating characteristic 0.63); single-unit activity did not differ between groups. Deep brain stimulation in the connectivity-derived 7-Tesla MRI subthalamic nucleus motor segment produced a superior clinical outcome; however, microelectrode recording did not accurately distinguish this subdivision within the subthalamic nucleus.

Tuning Neural Synchronization: The Role of Variable Oscillation Frequencies in Neural Circuits.

Brain oscillations emerge during sensory and cognitive processes and have been classified into different frequency bands. Yet, even within the same frequency band and between nearby brain locations, the exact frequencies of brain oscillations can differ. These frequency differences (detuning) have been largely ignored and play little role in current functional theories of brain oscillations. This contrasts with the crucial role that detuning plays in synchronization theory, as originally derived in physical systems. Here, we propose that detuning is equally important to understand synchronization in biological systems. Detuning is a critical control parameter in synchronization, which is not only important in shaping phase-locking, but also in establishing preferred phase relations between oscillators. We review recent evidence that frequency differences between brain locations are ubiquitous and essential in shaping temporal neural coordination. With the rise of powerful experimental techniques to probe brain oscillations, the contributions of exact frequency and detuning across neural circuits will become increasingly clear and will play a key part in developing a new understanding of the role of oscillations in brain function.

Thalamocortical coherence and causality in different sleep stages using deep brain stimulation recordings.

Previous research has shown an interplay between the thalamus and cerebral cortex during NREM sleep in humans, however the directionality of the thalamocortical synchronization is as yet unknown. In this study thalamocortical connectivity during different NREM sleep stages using sleep scalp electroencephalograms and local field potentials from the left and right anterior thalamus was measured in three epilepsy patients implanted with deep brain stimulation electrodes. Connectivity was assessed as debiased weighted phase lag index and granger causality between the thalamus and cortex for the NREM sleep stages N1, N2 and N3. Results showed connectivity was most prominently directed from cortex to thalamus. Moreover, connectivity varied in strength between the different sleep stages, but barely in direction or frequency. These results imply relatively stable thalamocortical connectivity during NREM sleep directed from the cortex to the thalamus.

Impact of Procedural Sedation on the Clinical Outcome of Microelectrode Recording Guided Deep Brain Stimulation in Patients with Parkinson's Disease.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) has become a routine treatment of advanced Parkinson's disease (PD). DBS surgery is commonly performed under local anesthesia (LA) to obtain reliable microelectrode recordings. However, procedural sedation and/or analgesia (PSA) is often desirable to improve patient comfort. The impact of PSA in addition to LA on outcome is largely unknown. Therefore, we performed an observational study to assess the effect of PSA compared to LA alone during STN DBS surgery on outcome in PD patients. METHODS: Seventy PD patients (22 under LA, 48 under LA + PSA) scheduled for STN DBS implantation were included. Dexmedetomidine, clonidine or remifentanil were used for PSA. The primary outcome was the change in Movement Disorders Society Unified Parkinson's Disease Rating Score III (MDS-UPDRS III) and levodopa equivalent daily dosage (LEDD) between baseline, one month before surgery, and twelve months postoperatively. Secondary outcome measures were motor function during activities of daily living (MDS-UPDRS II), cognitive alterations and surgical adverse events. Postoperative assessment was conducted in "on" stimulation and "on" medication conditions. RESULTS: At twelve months follow-up, UPDRS III and UPDRS II scores in "on" medication conditions were similar between the LA and PSA groups. The two groups showed a similar LEDD reduction and an equivalent decline in executive function measured by the Stroop Color-Word Test, Trail Making Test-B, and verbal fluency. The incidence of perioperative and postoperative adverse events was similar between groups. CONCLUSION: This study demonstrates that PSA during STN DBS implantation surgery in PD patients was not associated with differences in motor and non-motor outcome after twelve months compared with LA only.

Influence of Anesthesia and Clinical Variables on the Firing Rate, Coefficient of Variation and Multi-Unit Activity of the Subthalamic Nucleus in Patients with Parkinson's Disease.

BACKGROUND: Microelectrode recordings (MER) are used to optimize lead placement during subthalamic nucleus deep brain stimulation (STN-DBS). To obtain reliable MER, surgery is usually performed while patients are awake. Procedural sedation and analgesia (PSA) is often desirable to improve patient comfort, anxiolysis and pain relief. The effect of these agents on MER are largely unknown. The objective of this study was to determine the effects of commonly used PSA agents, dexmedetomidine, clonidine and remifentanil and patient characteristics on MER during DBS surgery. METHODS: Data from 78 patients with Parkinson's disease (PD) who underwent STN-DBS surgery were retrospectively reviewed. The procedures were performed under local anesthesia or under PSA with dexmedetomidine, clonidine or remifentanil. In total, 4082 sites with multi-unit activity (MUA) and 588 with single units were acquired. Single unit firing rates and coefficient of variation (CV), and MUA total power were compared between patient groups. RESULTS: We observed a significant reduction in MUA, an increase of the CV and a trend for reduced firing rate by dexmedetomidine. The effect of dexmedetomidine was dose-dependent for all measures. Remifentanil had no effect on the firing rate but was associated with a significant increase in CV and a decrease in MUA. Clonidine showed no significant effect on firing rate, CV or MUA. In addition to anesthetic effects, MUA and CV were also influenced by patient-dependent variables. CONCLUSION: Our results showed that PSA influenced neuronal properties in the STN and the dexmedetomidine (DEX) effect was dose-dependent. In addition, patient-dependent characteristics also influenced MER.

Combining Gamma With Alpha and Beta Power Modulation for Enhanced Cortical Mapping in Patients With Focal Epilepsy.

About one third of patients with epilepsy have seizures refractory to the medical treatment. Electrical stimulation mapping (ESM) is the gold standard for the identification of "eloquent" areas prior to resection of epileptogenic tissue. However, it is time-consuming and may cause undesired side effects. Broadband gamma activity (55-200 Hz) recorded with extraoperative electrocorticography (ECoG) during cognitive tasks may be an alternative to ESM but until now has not proven of definitive clinical value. Considering their role in cognition, the alpha (8-12 Hz) and beta (15-25 Hz) bands could further improve the identification of eloquent cortex. We compared gamma, alpha and beta activity, and their combinations for the identification of eloquent cortical areas defined by ESM. Ten patients with intractable focal epilepsy (age: 35.9 ± 9.1 years, range: 22-48, 8 females, 9 right handed) participated in a delayed-match-to-sample task, where syllable sounds were compared to visually presented letters. We used a generalized linear model (GLM) approach to find the optimal weighting of each band for predicting ESM-defined categories and estimated the diagnostic ability by calculating the area under the receiver operating characteristic (ROC) curve. Gamma activity increased more in eloquent than in non-eloquent areas, whereas alpha and beta power decreased more in eloquent areas. Diagnostic ability of each band was close to 0.7 for all bands but depended on multiple factors including the time period of the cognitive task, the location of the electrodes and the patient's degree of attention to the stimulus. We show that diagnostic ability can be increased by 3-5% by combining gamma and alpha and by 7.5-11% when gamma and beta were combined. We then show how ECoG power modulation from cognitive testing can be used to map the probability of eloquence in individual patients and how this probability map can be used in clinical settings to optimize ESM planning. We conclude that the combination of gamma and beta power modulation during cognitive testing can contribute to the identification of eloquent areas prior to ESM in patients with refractory focal epilepsy.

Spatial integration and its moderation by attention and acetylcholine.

Attention is often regarded as a mechanism by which attended objects become perceptually more salient, akin to increasing their contrast. We demonstrate by means of human psychophysics that attention is better described as a mechanism that reduces contextual integration, thereby ensuring that task irrelevant information is prevented from influencing the processing of task relevant information. To investigate possible neuronal bases of this phenomenon we studied the effects of attention on spatial integration in V1 of the macaque monkey. In line with our psychophysical results, attention directed to parafoveal locations reduced spatial integration by reducing the summation area of V1 neurons. Additionally we measured length tuning in V1 in the presence and absence of externally applied acetylcholine in V1 of the marmoset monkey. The effects of acetylcholine application and attention were largely similar. Acetylcholine reduced spatial integration by reducing the neuron's summation area. These data demonstrate that attention can alter perceptual and neuronal spatial integration, and that acetylcholine might contribute to task dependent receptive field dynamics.

Within-quadrant position and orientation specificity after extensive orientation discrimination learning is related to performance gains during late learning.

The last decade has seen the emergence of new views about the mechanisms underlying specificity (or, conversely, generalization) of visual skill learning. Here, we trained participants at orientation discrimination paradigm at a peripheral position to induce position and orientation specificity and to test its underlying mechanisms. Specifically, we aimed to test whether the within-quadrant spatial gradient of generalization is determined by cortical magnification, which would show that retinotopic plasticity contributes to learning and specificity. Additionally, we aimed to test whether late parts of the learning relate differently to specificity compared to early parts. This is relevant in the context of double training papers, which suggest that rule-based mechanisms of specificity in fast, early learning also would apply to late, slower learning. Our data showed partial but significant position and orientation specificity within quadrants. Interestingly, specificity was greatest for those participants who had continued to show threshold decreases during the last five sessions of training (late, asymptotic learning). Performance gains during early learning were less related to specificity. A trend for skill to spread over larger distances towards periphery than towards central vision suggested contributions to transfer of early visual areas showing cortical magnification of central vision. Control experiments however did not support this hypothesis. In summary, our study demonstrates significant specificity after extensive perceptual learning, and indicates that asymptotic learning recruits specific mechanisms that promote specificity, and that may not be recruited yet in early parts of the learning. The contributions of different mechanisms to early and late learning suggests that following these different learning periods, generalization relies on different principles and is subjected to different limits.