Abnormal center of mass feedback responses during balance: A potential biomarker of falls in Parkinson's disease.

Although Parkinson disease (PD) causes profound balance impairments, we know very little about how PD impacts the sensorimotor networks we rely on for automatically maintaining balance control. In young healthy people and animals, muscles are activated in a precise temporal and spatial organization when the center of body mass (CoM) is unexpectedly moved that is largely automatic and determined by feedback of CoM motion. Here, we show that PD alters the sensitivity of the sensorimotor feedback transformation. Importantly, sensorimotor feedback transformations for balance in PD remain temporally precise, but become spatially diffuse by recruiting additional muscle activity in antagonist muscles during balance responses. The abnormal antagonist muscle activity remains precisely time-locked to sensorimotor feedback signals encoding undesirable motion of the body in space. Further, among people with PD, the sensitivity of abnormal antagonist muscle activity to CoM motion varies directly with the number of recent falls. Our work shows that in people with PD, sensorimotor feedback transformations for balance are intact but disinhibited in antagonist muscles, likely contributing to balance deficits and falls.

Antagonist muscle activity during reactive balance responses is elevated in Parkinson's disease and in balance impairment.

BACKGROUND: Abnormal antagonist leg muscle activity could indicate increased muscle co-contraction and clarify mechanisms of balance impairments in Parkinson's disease (PD). Prior studies in carefully selected patients showed PD patients demonstrate earlier, longer, and larger antagonist muscle activation during reactive balance responses to perturbations. RESEARCH QUESTION: Here, we tested whether antagonist leg muscle activity was abnormal in a group of PD patients who were not selected for phenotype and most of whom had volunteered for exercise-based rehabilitation. METHODS: We compared antagonist activation during reactive balance responses to multidirectional support-surface translation perturbations in 31 patients with mild-moderate PD (age 68±9; H&Y 1-3; UPDRS-III 32±10) and 13 matched individuals (age 65±9). We quantified modulation of muscle activity (i.e., the ability to activate and inhibit muscles appropriately according to the perturbation direction) using modulation indices (MI) derived from minimum and maximum EMG activation levels observed across perturbation directions. RESULTS: Antagonist leg muscle activity was abnormal in unselected PD patients compared to controls. Linear mixed models identified significant associations between impaired modulation and PD (P<0.05) and PD severity (P<0.01); models assessing the entire sample without referencing PD status identified associations with balance ability (P<0.05), but not age (P = 0.10). SIGNIFICANCE: Antagonist activity is increased during reactive balance responses in PD patients who are not selected on phenotype and are candidates for exercise-based rehabilitation. This activity may be a mechanism of balance impairment in PD and a potential rehabilitation target or outcome measure.

Impaired set shifting is associated with previous falls in individuals with and without Parkinson's disease.

BACKGROUND: Individuals with Parkinson's disease (PD) are at increased risk for falls, which lead to substantial morbidity and mortality. Understanding the motor and non-motor impairments associated with falls in PD is critical to informing prevention strategies. In addition to motor symptoms, individuals with PD exhibit non-motor deficits, including impaired set shifting, an aspect of executive function related to cognitive flexibility that can be measured quickly with the Trailmaking Test. RESEARCH QUESTION: To determine whether impaired set shifting is associated with fall history in people with and without PD. METHODS: We examined associations between set shifting, PD status, and fall history (≥1 falls in the previous 6 months) in data from PD patients (n = 65) with and without freezing of gait (FOG) and community-dwelling neurologically-normal older adults (NON-PD) (n = 73) who had participated in our rehabilitation studies. RESULTS: Impaired set shifting was associated with previous falls after controlling for age, sex, overall cognitive function, PD status, FOG, and PD disease duration (OR = 1.29 [1.03-1.60]; P = 0.02). Consistent with literature, PD and FOG were also independently associated with increased fall prevalence (PD OR = 4.15 [95% CI 1.65-10.44], P < 0.01; FOG OR = 3.63 [1.22-10.80], P = 0.02). Although the strongest associations between set shifting and falling were observed among PD without FOG (OR = 2.11) compared to HOA (OR = 1.14) and PD with FOG (OR = 1.46), no statistically-significant differences were observed across groups. SIGNIFICANCE: Impaired set shifting is associated with previous falls in older adults with and without PD. Set shifting may be useful to include in fall risk assessments, particularly when global cognitive measures are within reference limits.

The effects of amphetamine, butorphanol, and their combination on cocaine self-administration.

There have been recent calls to examine the efficacy of drug-combination therapies in the treatment of substance use disorders. The purpose of the present study was to examine the ability of a novel stimulant-opioid combination to reduce cocaine self-administration, and to compare these effects to those of each drug administered alone. To this end, male Long-Evans rats were implanted with intravenous catheters and trained to self-administer cocaine under positive reinforcement contingencies. Once self-administration was acquired, rats were divided into four different groups and treated chronically for 20 days with (1) saline, (2) the psychomotor stimulant and monoamine releaser amphetamine, (3) the mu/kappa opioid agonist butorphanol, or (4) a combination of amphetamine and butorphanol. During chronic treatment, cocaine self-administration was examined on both fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. On the FR schedule, butorphanol significantly decreased cocaine self-administration, but this effect was not enhanced by amphetamine. On the PR schedule, amphetamine and butorphanol non-significantly decreased cocaine self-administration when administered alone but significantly decreased cocaine self-administration when administered in combination. These data suggest that under some conditions (e.g., when the response requirement of cocaine is high), a dual stimulant-opioid pharmacotherapy may be more effective than a single-drug monotherapy.

The EXCITE Trial: reacquiring upper-extremity task performance with early versus late delivery of constraint therapy.

OBJECTIVE: This study examines performance of Wolf Motor Function Test (WMFT) tasks in terms of the ability of EXCITE trial participants (who had suffered a stroke 3-9 months before recruitment) to complete the task within the timed interval. METHODS: Data were collected from participants who received constraint-induced movement therapy (CIMT) 3 to 9 months poststroke (CIMT-I, n = 106) or 15 to 21 months poststroke (CIMT-D, n = 116). Performance on the 15 timed WMFT tasks was converted into binary values, and changes in completion of the tasks were analyzed with generalized estimating equation methods, under the assumption of a binomial or Poisson process for completion. RESULTS: During CIMT, the CIMT-I group showed significant within-group improvements in 3 fine-movement tasks and in total noncompleted tasks (noncompletes), whereas the CIMT-D group did not (P ≤ .0036). CIMT-I improvement was significantly greater than CIMT-D improvement for the lifting pencil task and total noncompletes. During the year following CIMT, neither group showed significant changes in completion of WMFT tasks. Over all time intervals, only the CIMT-I group displayed significant improvement in several tasks and total noncompletes. Between groups, there were significant and almost-significant differences between the improvements of the 2 groups in 3 tasks requiring fine distal movement. CONCLUSION: Receiving CIMT earlier appears to improve reacquisition and retention of WMFT tasks, especially those requiring fine motor skills. Combined with earlier findings, these results indicate that improvements in existing motor abilities are possible with both immediate and delayed CIMT, but early CIMT is necessary for significant reacquisition of tasks.

Access to a running wheel decreases cocaine-primed and cue-induced reinstatement in male and female rats.

BACKGROUND: Relapse to drug use after a period of abstinence is a persistent problem in the treatment of cocaine dependence. Physical activity decreases cocaine self-administration in laboratory animals and is associated with a positive prognosis in human substance-abusing populations. The purpose of this study was to examine the effects of long-term access to a running wheel on drug-primed and cue-induced reinstatement of cocaine-seeking behavior in male and female rats. methods: Long-Evans rats were obtained at weaning and assigned to sedentary (no wheel) and exercising (access to wheel) groups for the duration of the study. After 6 weeks, rats were implanted with intravenous catheters and trained to self-administer cocaine for 14 days. After training, saline was substituted for cocaine and responding was allowed to extinguish, after which cocaine-primed reinstatement was examined in both groups. Following this test, cocaine self-administration was re-established in both groups for a 5-day period. Next, a second period of abstinence occurred in which both cocaine and the cocaine-associated cues were withheld. After 5 days of abstinence, cue-induced reinstatement was examined in both groups. RESULTS: Sedentary and exercising rats exhibited similar levels of cocaine self-administration, but exercising rats responded less than sedentary rats during extinction. In tests of cocaine-primed and cue-induced reinstatement, exercising rats responded less than sedentary rats, and this effect was apparent in both males and females. CONCLUSIONS: These data indicate that long-term access to a running wheel decreases drug-primed and cue-induced reinstatement, and that physical activity may be effective at preventing relapse in substance-abusing populations.

The effects of aerobic exercise on cocaine self-administration in male and female rats.

RATIONALE: In drug self-administration procedures, extended-access test sessions allow researchers to model maladaptive patterns of excessive and escalating drug intake that are characteristic of human substance-abusing populations. OBJECTIVES: The purpose of the present study was to examine the ability of aerobic exercise to decrease excessive and escalating patterns of drug intake in male and female rats responding under extended-access conditions. METHODS: Male and female Long-Evans rats were obtained at weaning and divided into sedentary (no running wheel) and exercising (running wheel) groups immediately upon arrival. After 6 weeks, rats were surgically implanted with intravenous catheters and allowed to self-administer cocaine under positive reinforcement contingencies. In experiment 1, cocaine self-administration was examined during 23-h test sessions that occurred every 4 days. In experiment 2, the escalation of cocaine intake was examined during daily 6-h test sessions over 14 consecutive days. RESULTS: In experiment 1, sedentary rats self-administered significantly more cocaine than exercising rats during uninterrupted 23-h test sessions, and this effect was apparent in both males and females. In experiment 2, sedentary rats escalated their cocaine intake to a significantly greater degree than exercising rats over the 14 days of testing. Although females escalated their cocaine intake to a greater extent than males, exercise effectively attenuated the escalation of cocaine intake in both sexes. CONCLUSIONS: These data indicate that aerobic exercise decreases maladaptive patterns of excessive and escalating cocaine intake under extended-access conditions.