Transcranial Alternating Current Stimulation (tACS) as a Treatment for Insomnia.

We investigated the effects of transcranial alternating stimulation (tACS) in patients with insomnia. Nine patients with chronic insomnia underwent two in-laboratory polysomnography, 2 weeks apart, and were randomized to receive tACS either during the first or second study. The stimulation was applied simultaneously and bilaterally at F3/M1 and F4/M2 electrodes (0.75 mA, 0.75 Hz, 5-minute). Sleep onset latency and wake after sleep onset dropped on the stimulation night but they did not reach statistical significance; however, there were significant improvements in spontaneous and total arousals, sleep quality, quality of life, recall memory, sleep duration, sleep efficiency, and daytime sleepiness.

Identifying perfusion deficits on CT perfusion images using temporal similarity perfusion (TSP) mapping.

OBJECTIVES: Deconvolution-derived maps of CT perfusion (CTP) data may be confounded by transit delays. We propose temporal similarity perfusion (TSP) analysis to decrease CTP maps' dependence on transit times and investigate its sensitivity to detect perfusion deficits. METHODS: CTP data of acute stroke patients obtained within 9 h of symptom onset was analyzed using a delay-insensitive singular value decomposition method and with TSP. The TSP method applies an iterative process whereby a pixel's highest Pearson's R value is obtained through comparison of a pixel's time-shifted signal density time-series curve and the average whole brain signal density time-series curve. Our evaluation included a qualitative and quantitative rating of deconvolution maps (MTT, CBV, and TTP), of TSP maps, and of follow-up CT. RESULTS: Sixty-five patients (mean 68 (SD 13) years, 34 male) were included. A perfusion deficit was identified in 90%, 86%, 65%, and 84% of MTT, TTP, CBV, and TSP maps. The agreement of MTT, TTP, and TSP with CT follow-up was comparable but noticeably lower for CBV. CBV had the best relationship with final infarct volume (R2 = 0.77, p < 0.001), followed by TSP (R2 = 0.63, p < 0.001). Intra-rater agreement of an inexperienced reader was higher for TSP than for CBV/MTT maps (kappa's of 0.79-0.84 and 0.63-0.7). Inter-rater agreement for experienced readers was comparable across maps. CONCLUSIONS: TSP maps are easier to interpret for inexperienced readers. Perfusion deficits detected by TSP are smaller which may suggest less dependence on transit delays although more investigation is required. KEY POINTS: • Temporal similarity perfusion mapping assesses CTP data based on similarities in signal time-curves. • TSP maps are comparable in perfusion deficit detection to deconvolution maps. • TSP maps are easier to interpret for inexperienced readers.

Temporal similarity perfusion mapping: A standardized and model-free method for detecting perfusion deficits in stroke.

INTRODUCTION: Interpretation of the extent of perfusion deficits in stroke MRI is highly dependent on the method used for analyzing the perfusion-weighted signal intensity time-series after gadolinium injection. In this study, we introduce a new model-free standardized method of temporal similarity perfusion (TSP) mapping for perfusion deficit detection and test its ability and reliability in acute ischemia. MATERIALS AND METHODS: Forty patients with an ischemic stroke or transient ischemic attack were included. Two blinded readers compared real-time generated interactive maps and automatically generated TSP maps to traditional TTP/MTT maps for presence of perfusion deficits. Lesion volumes were compared for volumetric inter-rater reliability, spatial concordance between perfusion deficits and healthy tissue and contrast-to-noise ratio (CNR). RESULTS: Perfusion deficits were correctly detected in all patients with acute ischemia. Inter-rater reliability was higher for TSP when compared to TTP/MTT maps and there was a high similarity between the lesion volumes depicted on TSP and TTP/MTT (r(18) = 0.73). The Pearson's correlation between lesions calculated on TSP and traditional maps was high (r(18) = 0.73, p<0.0003), however the effective CNR was greater for TSP compared to TTP (352.3 vs 283.5, t(19) = 2.6, p<0.03.) and MTT (228.3, t(19) = 2.8, p<0.03). DISCUSSION: TSP maps provide a reliable and robust model-free method for accurate perfusion deficit detection and improve lesion delineation compared to traditional methods. This simple method is also computationally faster and more easily automated than model-based methods. This method can potentially improve the speed and accuracy in perfusion deficit detection for acute stroke treatment and clinical trial inclusion decision-making.

Shifts in connectivity during procedural learning after motor cortex stimulation: A combined transcranial magnetic stimulation/functional magnetic resonance imaging study.

Inhibitory transcranial magnetic stimulation (TMS), of which continuous theta burst stimulation (cTBS) is a common form, has been used to inhibit cortical areas during investigations of their function. cTBS applied to the primary motor area (M1) depresses motor output excitability via a local effect and impairs procedural motor learning. This could be due to an effect on M1 itself and/or to changes in its connectivity with other nodes in the learning network. To investigate this issue, we used functional magnetic resonance imaging to measure changes in brain activation and connectivity during implicit procedural learning after real and sham cTBS of M1. Compared to sham, real cTBS impaired motor sequence learning, but caused no local or distant changes in brain activation. Rather, it reduced functional connectivity between motor (M1, dorsal premotor & supplementary motor areas) and visual (superior & inferior occipital gyri) areas. It also increased connectivity between frontal associative (superior & inferior frontal gyri), cingulate (dorsal & middle cingulate), and temporal areas. This potentially compensatory shift in coupling, from a motor-based learning network to an associative learning network accounts for the behavioral effects of cTBS of M1. The findings suggest that the inhibitory TMS affects behavior via relatively subtle and distributed effects on connectivity within networks, rather than by taking the stimulated area "offline".

Local but not long-range microstructural differences of the ventral temporal cortex in developmental prosopagnosia.

Individuals with developmental prosopagnosia (DP) experience face recognition impairments despite normal intellect and low-level vision and no history of brain damage. Prior studies using diffusion tensor imaging in small samples of subjects with DP (n=6 or n=8) offer conflicting views on the neurobiological bases for DP, with one suggesting white matter differences in two major long-range tracts running through the temporal cortex, and another suggesting white matter differences confined to fibers local to ventral temporal face-specific functional regions of interest (fROIs) in the fusiform gyrus. Here, we address these inconsistent findings using a comprehensive set of analyzes in a sample of DP subjects larger than both prior studies combined (n=16). While we found no microstructural differences in long-range tracts between DP and age-matched control participants, we found differences local to face-specific fROIs, and relationships between these microstructural measures with face recognition ability. We conclude that subtle differences in local rather than long-range tracts in the ventral temporal lobe are more likely associated with developmental prosopagnosia.

Practice structure improves unconscious transitional memories by increasing synchrony in a premotor network.

Sequence learning relies on formation of unconscious transitional and conscious ordinal memories. The influence of practice type on formation of these memories that compose skill and systems level neural substrates is not known. Here, we studied learning of transitional and ordinal memories in participants trained on motor sequences while scanned using fMRI. Practice structure was varied or grouped (mixing or grouping sequences during training, respectively). Memory was assessed 30 min and 1 week later. Varied practice improved transitional memory and enhanced coupling of the dorsal premotor cortex with thalamus, cerebellum, and lingual and cingulate regions and greater transitional memory correlated with this coupling. Thus, varied practice improves unconscious transitional memories in proportion to coupling within a cortico-subcortical network linked to premotor cortex. This result indicates that practice structure influences unconscious transitional memory formation and identifies underlying systems level mechanisms.

Crossmodal encoding of motor sequence memories.

In this study, we tested the hypothesis that exposure to specific auditory sequences could lead to the crossmodal induction of new motor memories. Twenty young, healthy participants memorized a melody without moving. Each tone in the memorized melody had previously been associated with a particular finger movement. For ten of the participants, the contour of the melody memorized was congruent to a subsequently performed, but never practiced, finger movement sequence (C group, n = 10). For the other ten participants, the melody memorized was incongruent to the subsequent finger movement sequence (InC group, n = 10). Results showed faster performance of the movement sequence in the C group than in the InC group. This difference in motor performance was most pronounced 6 h after melody learning and then dissipated over 30 days. These results provide evidence of a specific, crossmodal encoding of a movement sequence representation through an auditory sequence with the effect on motor performance lasting for several hours. The findings of this study are significant, as the formation of new motor memories through exposure to auditory stimuli may be useful in rehabilitation settings where the initial encoding of motor memories through physical training is disrupted.

Impact of conscious intent on chunking during motor learning.

Humans and other mammals learn sequences of movements by splitting them into smaller "chunks." Such chunks are defined by the faster speed of performance of groups of movements. The purpose of this report is to determine how conscious intent to learn impacts chunking, an issue that remains unknown. Here, we studied 80 subjects who either with or without conscious intent learned a motor sequence. Performance was tested before and up to 1-wk post-training. Chunk formation, carryover of chunks, and concatenation of chunks into longer chunks, all measures of motor chunking success, were determined at each time-point. We found that formation, carryover, and concatenation of chunks were comparable across groups and did not improve over the training session and subsequent testing times. Thus, motor learning progressed in the absence of improvements in chunking irrespective of conscious intent. These data suggest that mechanisms other than chunking contribute to successful motor learning with and without conscious intent.

Conscious recall of different aspects of skill memory.

Different mechanisms are involved in the formation of memories necessary for daily living. For example, different memory representations are formed for the practiced transitions between key-presses (i.e., pressing key "2" after "3" in "4-3-2-1") and for the ordinal position of each key-press (i.e., pressing key "2" in the third ordinal position in "4-3-2-1") in a motor sequence. Whether the resulting transition-based and ordinal-based memories (Song and Cohen, 2014) can be consciously recalled is unknown. Here, we studied subjects who over a week of training and testing formed transition and ordinal-based memory representations of skill for a 12-item sequence of key-presses. Afterwards, subjects were first asked to recall and type the trained sequence and then to perform random key-presses avoiding the trained sequence. The difference in the ability to purposefully recall and avoid a trained sequence represents conscious recall (Destrebecqz and Cleeremans, 2001). We report that (a) the difference in the ability to purposefully recall and to avoid the trained sequence correlated with ordinal-based but not with transition-based memory; (b) subjects with no ability to recall or avoid the trained sequence formed transition-based but not ordinal-based memories; and (c) subjects with full ability to recall and avoid the trained sequence formed both transition-based and ordinal-based memories. We conclude that ordinal-based memory can be voluntarily recalled when transition-based memory cannot, documenting a differential capacity to recall memories forming a motor skill. Understanding that different memories form a motor skill, with different neural substrates (Cohen and Squire, 1980), may help develop novel training strategies in neurorehabilitation of patients with brain lesions.

Practice and sleep form different aspects of skill.

Performance for skills such as a sequence of finger movements improves during sleep. This has widely been interpreted as evidence for a role of sleep in strengthening skill learning. Here we propose a different interpretation. We propose that practice and sleep form different aspects of skill. To show this, we train 80 subjects on a sequence of key-presses and test at different time points to determine the amount of skill stored in transition (that is, pressing '2' after '3' in '4-3-2-1') and ordinal (that is, pressing '2' in the third ordinal position in '4-3-2-1') forms. We find transition representations improve with practice and ordinal representations improve during sleep. Further, whether subjects can verbalize the trained sequence affects the formation of ordinal but not transition representations. Verbal knowledge itself does not increase over sleep. Thus, sleep encodes different representations of memory than practice, and may mediate conversion of memories between declarative and procedural forms.

White matter microstructural correlates of superior long-term skill gained implicitly under randomized practice.

We value skills we have learned intentionally, but equally important are skills acquired incidentally without ability to describe how or what is learned, referred to as implicit. Randomized practice schedules are superior to grouped schedules for long-term skill gained intentionally, but its relevance for implicit learning is not known. In a parallel design, we studied healthy subjects who learned a motor sequence implicitly under randomized or grouped practice schedule and obtained diffusion-weighted images to identify white matter microstructural correlates of long-term skill. Randomized practice led to superior long-term skill compared with grouped practice. Whole-brain analyses relating interindividual variability in fractional anisotropy (FA) to long-term skill demonstrated that 1) skill in randomized learners correlated with FA within the corticostriatal tract connecting left sensorimotor cortex to posterior putamen, while 2) skill in grouped learners correlated with FA within the right forceps minor connecting homologous regions of the prefrontal cortex (PFC) and the corticostriatal tract connecting lateral PFC to anterior putamen. These results demonstrate first that randomized practice schedules improve long-term implicit skill more than grouped practice schedules and, second, that the superior skill acquired through randomized practice can be related to white matter microstructure in the sensorimotor corticostriatal network.

Modifying somatosensory processing with non-invasive brain stimulation.

Purposeful manipulation of cortical plasticity and excitability within somatosensory regions may have therapeutic potential. Non-invasive brain stimulation (NBS) techniques such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) have shown promise towards this end with certain NBS protocols augmenting somatosensory processing and others down-regulating it. Here, we review NBS protocols which, when applied to primary somatosensory cortex, facilitate cortical excitability and tactile acuity (i.e., high-frequency repetitive TMS (rTMS), intermittent theta burst stimulation (TBS), paired associative stimulation (PAS) N20-5 to 0, anodal tDCS), and protocols that inhibit the same (i.e., low-frequency rTMS, continuous TBS, PAS N20-20, cathodal tDCS). Other studies have targeted multisensory regions of the brain to modulate somatosensory processing. These studies in full present a wide array of strategies in which NBS can be utilized to influence somatosensory processing in a behaviorally and clinically relevant capacity.

Consciousness and the consolidation of motor learning.

It is no secret that motor learning benefits from repetition. For example, pianists devote countless hours to performing complicated sequences of key presses, and golfers practice their swings thousands of times to reach a level of proficiency. Interestingly, the subsequent waking and sleeping hours after practice also play important roles in motor learning. During this time, a motor skill can consolidate into a more stable form that can lead to improved future performance without intervening practice. Though it is widely believed that sleep is crucial for this consolidation of motor learning, this is not generally true. In many instances only day-time consolidates motor learning, while in other instances neither day-time nor sleep consolidates learning. Recent studies have suggested that conscious awareness during motor training can determine whether sleep or day-time plays a role in consolidation. However, ongoing studies suggest that this explanation is also incomplete. In addition to conscious awareness, attention is an important factor to consider. This review discusses how attention and conscious awareness interact with day and night processes to consolidate a motor memory.

Evidence for parallel explicit and implicit sequence learning systems in older adults.

Some research indicates that explicit learning of a sequence can impair procedural learning, particularly in populations with reduced cognitive capacity. However, these studies usually do not distinguish the effects of explicit processes on procedural learning from their effects on performance. The current study demonstrates that explicit learning affects performance, but not procedural sequence learning, in healthy older adults even when sequences are complex. These findings support capacity-independent theories which propose that procedural and declarative learning operate in parallel.

Perceptual sequence learning in a serial reaction time task.

In the serial reaction time task (SRTT), a sequence of visuo-spatial cues instructs subjects to perform a sequence of movements which follow a repeating pattern. Though motor responses are known to support implicit sequence learning in this task, the goal of the present experiments is to determine whether observation of the sequence of cues alone can also yield evidence of implicit sequence learning. This question has been difficult to answer because in previous research, performance improvements which appeared to be due to implicit perceptual sequence learning could also be due to spontaneous increases in explicit knowledge of the sequence. The present experiments use probabilistic sequences to prevent the spontaneous development of explicit awareness. They include a training phase, during which half of the subjects observe and the other half respond, followed by a transfer phase in which everyone responds. Results show that observation alone can support sequence learning, which translates at transfer into equivalent performance as that of a group who made motor responses during training. However, perceptual learning or its expression is sensitive to changes in target colors, and its expression is impaired by concurrent explicit search. Motor-response based learning is not affected by these manipulations. Thus, observation alone can support implicit sequence learning, even of higher order probabilistic sequences. However, perceptual learning can be prevented or concealed by variations of stimuli or task demands.

Sleep does not benefit probabilistic motor sequence learning.

It has become widely accepted that sleep-dependent consolidation occurs for motor sequence learning based on studies using finger-tapping tasks. Studies using another motor sequence learning task [the serial response time task (SRTT)] have portrayed a more nuanced picture of off-line consolidation, involving both sleep-dependent and daytime consolidation, as well as modifying influences of explicit awareness. The present study used a variant of the SRTT featuring probabilistic sequences to investigate off-line consolidation. Probabilistic sequences confer two advantages: first, spontaneous explicit awareness does not occur, and second, sequence learning measures are continuous, making it easier to separate general skill from sequence-specific learning. We found that sleep did not enhance general skill or sequence-specific learning. In contrast, daytime enhancement occurred for general skill but not for sequence-specific learning. Overall, these results suggest that motor learning does not always undergo consolidation with sleep.

Implicit probabilistic sequence learning is independent of explicit awareness.

Studies into interactions between explicit and implicit motor sequence learning have yielded mixed results. Some of these discrepancies have been attributed to difficulties in isolating implicit learning. In the present study, the effect of explicit knowledge on implicit learning was investigated using a modified version of the Alternating Serial Response Time (ASRT) task, a probabilistic sequence learning paradigm that yields continuous and relatively pure measures of implicit learning. Results revealed that implicit learning occurred to the same extent, whether or not subjects had explicit knowledge. Some evidence, however, indicated that explicit knowledge could interfere with the expression of implicit learning early in training. In addition, there were dissociations between learning measures, in that reaction time and accuracy were differentially affected by explicit knowledge. These findings indicate that implicit sequence learning occurs independently of explicit knowledge, and help to explain previous discrepant findings.