Brain Mechanisms of Pain and Dysautonomia in Diabetic Neuropathy: Connectivity Changes in Thalamus and Hypothalamus.

CONTEXT: About one-third of diabetic patients suffer from neuropathic pain, which is poorly responsive to analgesic therapy and associated with greater autonomic dysfunction. Previous research on diabetic neuropathy mainly links pain and autonomic dysfunction to peripheral nerve degeneration resulting from systemic metabolic disturbances, but maladaptive plasticity in the central pain and autonomic systems following peripheral nerve injury has been relatively ignored. OBJECTIVE: This study aimed to investigate how the brain is affected in painful diabetic neuropathy (PDN), in terms of altered structural connectivity (SC) of the thalamus and hypothalamus that are key regions modulating nociceptive and autonomic responses. METHODS: We recruited 25 PDN and 13 painless (PLDN) diabetic neuropathy patients, and 27 healthy adults as controls. The SC of the thalamus and hypothalamus with limbic regions mediating nociceptive and autonomic responses was assessed using diffusion tractography. RESULTS: The PDN patients had significantly lower thalamic and hypothalamic SC of the right amygdala compared with the PLDN and control groups. In addition, lower thalamic SC of the insula was associated with more severe peripheral nerve degeneration, and lower hypothalamic SC of the anterior cingulate cortex was associated with greater autonomic dysfunction manifested by decreased heart rate variability. CONCLUSION: Our findings indicate that alterations in brain structural connectivity could be a form of maladaptive plasticity after peripheral nerve injury, and also demonstrate a pathophysiological association between disconnection of the limbic circuitry and pain and autonomic dysfunction in diabetes.

Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: altered thalamic connectome and its associations with skin nerve degeneration.

ABSTRACT: Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.

Contextual interference enhances motor learning through increased resting brain connectivity during memory consolidation.

Increasing contextual interference (CI) during practice benefits learning, making it a desirable difficulty. For example, interleaved practice (IP) of motor sequences is generally more difficult than repetitive practice (RP) during practice but leads to better learning. Here we investigated whether CI in practice modulated resting-state functional connectivity during consolidation. 26 healthy adults (11 men/15 women, age = 23.3 ±â€¯1.3 years) practiced two sets of three sequences in an IP or RP condition over 2 days, followed by a retention test on Day 5 to evaluate learning. On each practice day, functional magnetic resonance imaging (fMRI) data were acquired during practice and also in a resting state immediately after practice. The resting-state fMRI data were processed using independent component analysis (ICA) followed by functional connectivity analysis, showing that IP on Day 1 led to greater resting connectivity than RP between the left premotor cortex and left dorsolateral prefrontal cortex (DLPFC), bilateral posterior cingulate cortices, and bilateral inferior parietal lobules. Moreover, greater resting connectivity after IP than RP on Day 1, between the left premotor cortex and the hippocampus, amygdala, putamen, and thalamus on the right, and the cerebellum, was associated with better learning following IP. Mediation analysis further showed that the association between enhanced resting premotor-hippocampal connectivity on Day 1 and better retention performance following IP was mediated by greater task-related functional activation during IP on Day 2. Our findings suggest that the benefit of CI to motor learning is likely through enhanced resting premotor connectivity during the early phase of consolidation.

Benefit of interleaved practice of motor skills is associated with changes in functional brain network topology that differ between younger and older adults.

Practicing tasks arranged in an interleaved manner generally leads to superior retention compared with practicing tasks repetitively, a phenomenon known as the contextual interference (CI) effect. We investigated the brain network of motor learning under CI, that is, the CI network, and how it was affected by aging. Sixteen younger and 16 older adults practiced motor sequences arranged in a repetitive or an interleaved order over 2 days, followed by a retention test on day 5 to evaluate learning. Network analysis was applied to functional MRI data on retention to define the CI network by identifying brain regions with greater between-region connectivity after interleaved compared with repetitive practice. CI effects were present in both groups but stronger in younger adults. Moreover, CI networks in younger adults exhibited efficient small-world topology, with a significant association between higher network centrality and better learning after interleaved practice. Older adults did not show such favorable network properties. Our findings suggest that aging affects the efficiency of brain networks underlying enhanced motor learning after CI practice.

Interleaved practice enhances skill learning and the functional connectivity of fronto-parietal networks.

Practice of tasks in an interleaved order generally induces superior learning compared with practicing in a repetitive order, a phenomenon known as the contextual-interference (CI) effect. Increased neural activity during interleaved over repetitive practice has been associated with the beneficial effects of CI. Here, we used psychophysiological interaction (PPI) analysis to investigate whether the neural connectivity of the dorsal premotor (PM) and the dorsolateral prefrontal (DLPFC) cortices changes when motor sequences are acquired through interleaved practice. Sixteen adults practiced a serial reaction time task where a set of three 4-element sequences were arranged in a repetitive or in an interleaved order on 2 successive days. On Day 5, participants were tested with practiced sequences to evaluate retention. A within-subjects design was used so that participants practiced sequences in the other condition (repetitive or interleaved) 2-4 weeks later. Functional magnetic resonance images were acquired during practice and retention. On Day 2 of practice, there was greater inter-regional functional connectivity in the interleaved compared with the repetitive condition for both PM-seeded and DLPFC-seeded connectivity. The increased functional connectivity between both seeded regions and sensorimotor cortical areas correlated with the benefit of interleaved practice during later retention. During retention, a significant PPI effect was found in DLPFC-seeded connectivity, with increased DLPFC-supplementary motor area connectivity correlated with the benefits of interleaved practice. These data suggest that interleaved practice benefits learning by enhancing coordination of sensorimotor cortical regions, and superior performance of sequences learned under CI is characterized by increased functional connectivity in frontal cortex.

Enhanced motor learning in older adults is accompanied by increased bilateral frontal and fronto-parietal connectivity.

We recently demonstrated that older adults can benefit as much as younger adults from learning skills in an interleaved manner. Here we investigate whether optimized learning through interleaved practice (IP) is associated with changes in inter-regional brain connectivity and whether younger and older adults differ in such brain-behavior correlations. Younger and older adults practiced a set of three 4-element motor sequences in a repetitive or in an interleaved order for 2 consecutive days. Retention of the practiced sequences was evaluated 3 days after practice with functional images acquired simultaneously. A within-subject design was used so that subjects practiced sequences in the other condition (repetitive or interleaved) 2-4 weeks later. Using the psychophysiological interaction (PPI) analysis approach, we found that IP led to higher functional connectivity between the right and left dorsal lateral prefrontal cortex (DLPFC) and between the dorsal premotor cortex (PMd) and inferior parietal lobule (IPL) in older adults. Moreover, increased connectivity between these regions was significantly associated with the learning benefits of IP. In contrast, in younger adults, enhanced learning as a result of IP was associated with increased connectivity between DLPFC and the supplementary motor area (SMA) and the inferior frontal gyrus. These data suggest that though younger and older gain similar behavioral benefits from interleaved training, aging may alter the operation of brain networks underlying such optimized learning.

Brain-behavior correlates of optimizing learning through interleaved practice.

Understanding how to make learning more efficient and effective is an important goal in behavioral neuroscience. The notion of "desirable difficulties" asserts that challenges for learners during study result in superior learning. One "desirable difficulty" that has a robust benefit on learning is contextual interference (CI), in which different tasks are practiced in an interleaved order rather than in a repetitive order. This study is the first to combine functional imaging and paired-pulse transcranial magnetic stimulation to analyze the neural basis of the CI effect in skill learning. Difficulty during practice of a serial reaction time task was manipulated by presenting sequences of response locations in a repetitive or an interleaved order. Participants practiced 3 sequences for 2 days and were tested on day 5 to examine sequence-specific learning. During practice, slower response times (RT), greater frontal-parietal blood-oxygen-level-dependent (BOLD) signal, and higher motor cortex (M1) excitability were found in the interleaved condition compared to the repetitive condition. Consistent with the CI effect, we found faster RT, decreased BOLD signal in frontal-parietal regions, and greater M1 excitability during the day 5 retention task when subjects had practiced interleaved sequences. Correlation analyses indicated that greater BOLD signal in contralateral sensorimotor region and M1 excitability during interleaved practice were interrelated. Furthermore, greater BOLD signal in prefrontal, premotor and parietal areas and greater M1 excitability during interleaved practice correlated with the benefit of interleaved practice on retention. This demonstrates that interleaved practice induces interrelated changes in both cortical hemodynamic responses and M1 excitability, which likely index the formation of enhanced memory traces and efficient long-term retrieval.

Contextual interference effects in sequence learning for young and older adults.

Practice of different tasks in a random order induces better retention than practicing them in a blocked order, a phenomenon known as the contextual interference (CI) effect. Our purpose was to investigate whether the CI effect exists in sequence learning, such that practicing different sequences in a random order will result in better learning of sequences than practicing them in blocks, and whether this effect is affected by aging. Subjects practiced a serial reaction time task where a set of three 4-element sequences were arranged in blocks or in a random order on 2 successive days. Subjects were divided into 4 groups based on a 2-GROUP (young or old) by 2-ORDER (random or blocked practice) between-subject design. Three days after practice (Day 5), subjects were tested with practiced and novel sequences to evaluate sequence-specific learning. The results replicate the CI effect in sequence learning in both young and older adults. Older adults retained sequences better when trained in a random condition than in a blocked condition, although the random condition incurs greater task switching costs in older adults during practice. Our study underscores the distinction between age-related effects on learning vs. performance, and offers practical implications for enhancing skill learning in older adults.

Neural correlates of the contextual interference effect in motor learning: a transcranial magnetic stimulation investigation.

The authors applied transcranial magnetic stimulation (TMS) to investigate the causal role of the primary motor cortex (M1) for the contextual-interference effect in motor learning. Previous work using a nonfocal TMS coil suggested a casual role for M1 during high-interference practice conditions, but this hypothesis has not yet been proven. In the 1st experiment, participants practiced 3 rapid elbow flexion-extension tasks in either a blocked or random order, with learning assessed by a delayed retention test. TMS was delivered immediately after feedback during practice using a circular coil, centered over the contralateral M1. Each participant practiced with 1 of 3 TMS conditions: no TMS, real TMS, or sham TMS. Although no significant differences were observed between groups during acquisition, retention of the random group was better than the blocked group. The learning benefits of random practice were attenuated in the real-TMS condition, but not in the sham-TMS or no-TMS conditions. In the second experiment, the authors studied the effects of suprathreshold TMS and subthreshold TMS over M1, lateral premotor cortex, and peripheral arm stimulation using a focal figure-8 coil on motor learning under random practice conditions. The authors found that only suprathreshold TMS on M1 produced significant disruption of retention compared to the other stimulation conditions. Results suggest that a high-threshold neuronal population within M1 is causally important for enhanced retention following random, but not block, practice. Results also support the early intertrial interval as a critical period of M1 activity during practice. Overall, these results suggest neural circuits within M1 contribute to motor learning processing that depends on learners' training experience. Results contribute to knowledge of the critical and specific role that M1 plays in generating a learning advantage following high-interference practice conditions.

Age affects the attentional demands of stair ambulation: evidence from a dual-task approach.

BACKGROUND: Approximately 75% of all injury-producing falls on steps for people of all ages occur in people 65 years of age and older. Diminished attentional capacity contributes to fall risk in older adults, particularly when task demands are high. OBJECTIVE: The purpose of this study was to compare the attentional demands of ascending and descending a set of stairs (stair ambulation) in older adults and younger adults. DESIGN: This was a nonblinded, prospective, single-site, observational cohort study. METHODS: Ten older (>65 years of age) and 10 younger (21-33 years of age) adults without disabilities were recruited. A dual-task approach was used for 2 task conditions: the first task was standing and responding verbally to an unanticipated auditory tone as quickly as possible (probe task), and the second task was ascending or descending a set of stairs with the same probe task. A 2-factor (group x task) analysis of variance with repeated measures on task (standing and stair ambulation) was performed for voice response time (VRT). Significance for the analysis was set at P<.05. RESULTS: The group x task interaction was significant for VRT. Post hoc analyses indicated that during stair ambulation, the VRT for older adults was significantly longer than that for younger adults. For the standing task, the VRTs (X+/-SD) were similar for younger (322+/-65 milliseconds) and older (306+/-22 milliseconds) participants. For stair ascent and descent, the average VRTs were more than 100 milliseconds longer for older participants (493+/-113 and 470+/-127 milliseconds, respectively) than for younger participants (365+/-56 and 356+/-67 milliseconds, respectively). LIMITATIONS: Because of the small sample size and generally fit older group, generalization of findings to older people at risk for falls is not recommended until further research is done. CONCLUSIONS: The results demonstrated that although both older and younger adults required similar attentional resources for the standing task, older adults required significantly more resources during stair ambulation. The findings suggested that the dual-task method used here provided a clinically useful measure for detecting important changes in attentional demands in older adults who are healthy.

Differences in sonographic characteristics of the vastus medialis obliquus between patients with patellofemoral pain syndrome and healthy adults.

BACKGROUND: There is controversy regarding the relationship between patellofemoral pain syndrome (PFPS) and insufficiency of the vastus medialis obliquus (VMO). The conventional clinical practice of VMO strengthening for PFPS has been challenged for lack of evidence. The purpose of this study was to observe the difference in sonographic findings of the VMO between patients with PFPS and healthy adults. HYPOTHESIS: The morphological characteristics of the VMO are different between patients with PFPS and healthy adults. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Fifty-four patients with PFPS and 54 age-, gender-, body height-, and body weight-matched healthy adults as controls were enrolled in the study to measure by sonography the insertion level, fiber angle, and volume of the VMO at its insertional portion to detect differences between patients with PFPS and healthy controls. RESULTS: The insertion level, fiber angle, and VMO volume were all significantly smaller in the PFPS group than in the control group (P < .05). Multivariate analysis of variance has revealed a Wilks lambda value of .845 and an F value of 5.640 (P = .001). CONCLUSION: There was a significant difference in the 3 VMO measures between patients with PFPS and the healthy controls. Individuals might be predisposed to PFPS by different VMO characteristics, including insertion level and fiber angle. The current study cannot determine whether the observed morphological differences were the results of atrophy in response to pain or if they represent dysplasia that was predisposed to pain development. The clinical manifestations of VMO characteristics should be thoroughly investigated in other populations. CLINICAL RELEVANCE: The function of the VMO is important to consider in the rehabilitation of patients with PFPS.

Efficacy of 2 non-weight-bearing interventions, proprioception training versus strength training, for patients with knee osteoarthritis: a randomized clinical trial.

STUDY DESIGN: Randomized clinical trial. OBJECTIVE: To investigate the clinical and functional efficacy of 2 different non-weight-bearing exercise regimens, proprioceptive training (PrT) versus strength training (ST), for patients with knee osteoarthritis (OA). BACKGROUND: Both strength and proprioceptive training are important interventions for individuals with knee OA. The benefits of weight-bearing exercises are generally recognized in the clinical setting. However, exercising in a standing or weight-bearing position may aggravate symptoms in patients with knee OA. METHODS AND MEASURES: One hundred eight patients were randomly assigned to the PrT, ST, or no exercise (control) group for an 8-week intervention. Both the PrT and ST interventions consisted of non-weight-bearing exercises. Western Ontario and McMaster Universities Osteoarthritis Index-pain (WOMAC-pain) and -function scores, walking time on 3 different terrains, knee strength, and absolute knee reposition error were assessed before and after intervention. Data were analyzed using mixed-model ANOVAs. RESULTS: Both PrT and ST significantly improved WOMAC-pain and -function score after intervention (P<.008). The improvement secondary to ST in the WOMAC-function scores (17.2 points) and for knee extension strength (10.3-14.9 Nm) was greater than the minimally clinically important difference for these measurements. The PrT group demonstrated greater improvement in walking time on a spongy surface and knee reposition error than the other 2 groups. No improvements were apparent in the control group. CONCLUSION: Both types of non-weight-bearing exercises (PrT and ST) significantly improved outcomes in this study. PrT led to greater improvements in proprioceptive function, while ST resulted in a greater increase in knee extensor muscle strength.

The effects of quadriceps contraction on different patellofemoral alignment subtypes: an axial computed tomography study.

STUDY DESIGN: Controlled laboratory study. BACKGROUND: The effect of quadriceps contraction on patellar alignment in patients with patellofemoral pain syndrome (PFPS) is debated and may vary based on patellar alignment subtypes measured with the quadriceps relaxed. OBJECTIVES: To determine if the effects of quadriceps contraction on patellar alignment differs (1) with respect to patellar alignment subtype in individuals with PFPS and (2) between symptomatic and asymptomatic knees in individuals with unilateral PFPS. METHODS AND MEASURES: Seventy-eight individuals, 47 with bilateral and 31 with unilateral PFPS, participated in the study. On axial computed tomography images with the knee in extension with quadriceps relaxed as well as contracted, patellar lateral condyle index (PLCI) and patellar tilt angle (PTA) were measured and analyzed. Based on the median PLCI and PTA alignment values measured with quadriceps relaxed for the 78 subjects, 4 subgroups of subjects were created: type 1, laterally displaced; type 2, laterally displaced and tilted; type 3, laterally tilted; and type 4, neither. RESULTS: Quadriceps contraction caused an increase in PLCI in all patellar alignment types (P<.01), with no difference in the magnitude of the increase between types (P>.05). PTA decreased with quadriceps contraction in the subjects with the type 3 initial patellar alignment (P<.01), with a significant difference in the change in patellar alignment between the subjects with type 3 and type 1 initial patellar alignment (P=.004). For the 31 subjects with unilateral PFPS, quadriceps contraction caused a similar change in PLCI and PTA in both the symptomatic and asymptomatic knees. CONCLUSIONS: The initial position of the patella with the quadriceps relaxed did not influence the change in PLCI with quadriceps contraction. For the 31 subjects with PFPS, there was no difference in initial alignment as well as in change of alignment with quadriceps contraction between symptomatic and asymptomatic knees.

Neural correlate of the contextual interference effect in motor learning: a kinematic analysis.

The contextual interference (CI) effect affirms that learning is enhanced when interference during practice is high, such as when participants practice multiple tasks in a random order. Previous research showed a distinct response in the cortical motor (CM) regions of participants performing under high CI practice conditions compared with low CI conditions. Specifically, there was increased corticomotor activity in a high CI condition when participants practiced 3 arm tasks, each with specific spatial and temporal requirements. Using disruptive transcranial magnetic stimulation (TMS), the authors' purpose was to determine whether CM is preferentially processing the spatial, temporal, or both parameters of the task during high CI practice. Participants were randomized to 1 of 6 practice conditions derived from 3 stimulation conditions (no TMS, TMS, sham TMS) and 2 CI conditions (blocked [low CI] and random [high CI]). The authors measured performance accuracy in movement timing (temporal) and amplitude (spatial) across practice and no-stimulation recall phases. TMS perturbation deterred learning of movement timing under random, but not blocked, practice order; the authors did not observe this in spatial parameter learning. The authors' data suggest that increased corticomotor activity during high CI practice may reflect preferential processing of the temporal parameter of the task.

Contextual interference effect: elaborative processing or forgetting-reconstruction? A post hoc analysis of transcranial magnetic stimulation-induced effects on motor learning.

The elaborative-processing and forgetting-reconstruction hypotheses are the 2 principal explanations for the contextual interference (CI) effect. The present authors' purpose was to identify which of these 2 hypotheses better accounts for the CI effect. They synchronized single transcranial magnetic stimulation (TMS) pulses to each intertrial interval to modulate information processing during Blocked and Random Practice conditions. Participants practiced 3 arm tasks with either a Blocked or Random Practice order. The 3 stimulation conditions (No TMS, TMS, Sham TMS) by 2-practice order (Blocked, Random) between-participant design resulted in 6 experimental groups. Without TMS, motor learning increased under Random Practice. With TMS, this learning benefit diminished. These results support the elaborative-processing hypothesis by showing that perturbing information processing, evoked by Random Practice, deteriorates the learning benefit. Unlike the prediction of the forgetting-reconstruction hypothesis, adding perturbation during Blocked Practice did not significantly enhance motor learning.

The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson's disease.

OBJECTIVES: To obtain preliminary data on the effects of high-intensity exercise on functional performance in people with Parkinson's disease (PD) relative to exercise at low and no intensity and to determine whether improved performance is accompanied by alterations in corticomotor excitability as measured through transcranial magnetic stimulation (TMS). DESIGN: Cohort (prospective), randomized controlled trial. SETTING: University-based clinical and research facilities. PARTICIPANTS: Thirty people with PD, within 3 years of diagnosis with Hoehn and Yahr stage 1 or 2. INTERVENTIONS: Subjects were randomized to high-intensity exercise using body weight-supported treadmill training, low-intensity exercise, or a zero-intensity education group. Subjects in the 2 exercise groups completed 24 exercise sessions over 8 weeks. Subjects in the zero-intensity group completed 6 education classes over 8 weeks. MAIN OUTCOME MEASURES: Unified Parkinson's Disease Rating Scales (UPDRS), biomechanic analysis of self-selected and fast walking and sit-to-stand tasks; corticomotor excitability was assessed with cortical silent period (CSP) durations in response to single-pulse TMS. RESULTS: A small improvement in total and motor UPDRS was observed in all groups. High-intensity group subjects showed postexercise increases in gait speed, step and stride length, and hip and ankle joint excursion during self-selected and fast gait and improved weight distribution during sit-to-stand tasks. Improvements in gait and sit-to-stand measures were not consistently observed in low- and zero-intensity groups. The high-intensity group showed lengthening in CSP. CONCLUSIONS: The findings suggest the dose-dependent benefits of exercise and that high-intensity exercise can normalize corticomotor excitability in early PD.

Effect of task practice order on motor skill learning in adults with Parkinson disease: a pilot study.

BACKGROUND AND PURPOSE: Random practice of motor tasks has been shown to enhance motor learning. The purpose of this study was to investigate the effects of task practice order (random, blocked) on motor learning in adults with Parkinson disease (PD). SUBJECTS: Twenty adults with mild PD and 20 age-matched adults (controls) participated in the study. METHODS: Participants in both groups (PD and control) practiced 3 movement tasks with either a blocked or a random practice order. This 2 participant group x 2 practice order design resulted in 4 experimental groups. The Trail Making Test was administered to all participants to determine task-switching capability. Motor performance on the arm movement tasks was quantified on the basis of the root-mean-square error difference between the goal movement task and each participant's response. RESULTS: The task-switching capability of the control group was superior to that of the PD group. For acquisition, in general, participants in the control group performed with significantly less error than participants in the PD group. For retention, participants in the control group who practiced with a random order performed more accurately than participants in the control group who practiced with a blocked order. However, for the PD group, the findings were reversed; participants who practiced with a blocked order performed more accurately than participants who practiced with a random order. These findings resulted in a group x practice order interaction. DISCUSSION AND CONCLUSION: These pilot study data suggest that, contrary to the findings for age-matched control learners, for learners with mild PD, a blocked practice order may be better than a random practice order for motor learning.