Resting state functional connectivity is associated with cognitive dysfunction in non-demented people with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) can result in cognitive impairment. Executive dysfunction often appears early, followed by more widespread deficits later in the course of the disease. Disruption of parallel basal ganglia thalamo-cortical loops that subserve motor and cognitive function has been described in PD. However, there is emerging evidence that the default mode network, a cortical network that is active at rest with reduced activation during task performance, may also play a role in disease related cognitive decline. OBJECTIVE: To determine the relative contribution of the executive control and default mode networks to parkinsonian executive dysfunction in medicated non-demented patients. METHODS: We used BOLD fMRI to measure resting state functional connectivity in the executive control and default mode (DM) networks, and examined switching, processing speed, working memory/attention and motor performance in 14 medicated non-demented PD participants and 20 controls. RESULTS: Performance on neuropsychological measures was similar across groups. Functional connectivity was not different across disease conditions in the executive control network. DMN functional connectivity was decreased in the PD group, specifically between posterior cingulate, medial prefrontal, and inferior parietal nodes. Greater DMN functional connectivity was associated with faster processing speed in the PD group. CONCLUSIONS: The continuous relationship between DMN disconnection and executive task performance indicates a possible biological contributor to parkinsonian cognitive deficits. The dynamics of executive control network change may be different than that of the DMN, suggesting less sensitivity to early cognitive deficits.

Efficacy of tailored computer-based neurorehabilitation for improvement of movement initiation in Parkinson's disease.

While Parkinson's disease (PD) is considered a motor disorder, motor signs of PD can be exacerbated by cognitive dysfunction. We evaluated the efficacy of a computer-based cognitive rehabilitation training program designed to improve motor-related executive function. Thirty people with PD and 21 controls participated in the 10-day training. Training consisted of a two-phase button press task. First, subjects produced an externally cued (EC) digit sequence, typing numbers displayed on the computer screen. Second, subjects were prompted to generate the same sequence in the absence of the number display (internally represented sequence, IR). Sequence length was automatically adjusted to maintain 87% correct performance. Participants were evaluated before and after training using a fixed version of the training task, and generalization of training was assessed using measures involving IR motor sequencing, switching and activities of daily living. PD participants were divided into two groups, those who showed impairment in IR motor sequence production prior to training (N=14) and those whose performance was similar to controls (N=16). Following training the impaired PD group showed significantly greater reduction in sequence initiation and completion time and in error rate for IR conditions compared to the unimpaired PD and control groups. All groups improved on Trails B-A, and pre-training Trails B was identified as a predictor of training-based improvement in IR sequence completion time and error rate. Our findings highlight the importance of neurorehabilitation tailored to the specific cognitive deficits of the PD patient.

Inter- and intralimb oscillator coupling in parkinsonian tremor.

This study reports the findings of an analysis of temporal correlation between tremor of different muscles of the same and different limbs in four patients with Parkinson's disease. Spectral coherence methods were used for determining whether simultaneously occurring oscillations in the electromyograms of different muscles are statistically coupled. The incidence of significant coherence was considerably higher for muscle pairs in the same limb than for pairs in different limbs; Parkinson's disease tremor is coupled within but not between limbs. Because the characteristics of tremor are known to vary under different behavioral situations, the intralimb coupling was examined for different tasks. A mental arithmetic task resulted in an increase in the coherence between muscles of the same limb, whereas the finger-to-nose task decreased the coherence. No significant change in coherence was found for a postural task. The amplitude and regularity of tremor electromyography showed changes analogous to those in coherence. These results support the hypothesis that tremor in different limbs results from the activity of several neural circuits oscillating independently. The results also emphasize the value of these methods for rigorously characterizing tremor, in relation to disease state, behavioral conditions, and the selection of treatment strategies.

Extent and role of multisegmental coupling in the Lamprey spinal locomotor pattern generator.

Timing of oscillatory activity along the longitudinal body axis is critical for locomotion in the lamprey and other elongated animals. In the lamprey spinal locomotor central pattern generator (CPG), intersegmental coordination is thought to arise from the pattern of extensive connections made by propriospinal interneurons. However, the mechanisms responsible for intersegmental coordination remain unknown, in large part because of the difficulty in obtaining quantitative information on these multisegmental fibers. System-level experiments were performed on isolated 50-segment preparations of spinal cord of adult silver lampreys, Ichthyomyzon unicuspis, to determine the dependence of CPG performance on multisegmental coupling. Coupling was manipulated through use of an experiment chamber with movable partitions, which allowed separate application of solution to rostral, middle, and caudal regions of the spinal cord preparation. During control trials, fictive locomotion, induced by bath application of D-glutamate in all three regions, was recorded extracellularly from ventral roots. Local synaptic activity in a variable number of middle segments was subsequently blocked with a low-Ca(2+), high-Mn(2+) saline solution in the middle compartment, whereas conduction in axons spanning the middle segments was unaffected. Spectral analysis was used to assess the effects of blocking propriospinal coupling on intersegmental phase lag, rhythm frequency, correlation, and variability. Significant correlation and a stable phase lag between the rostral and caudal regions of the spinal cord preparation were maintained during block of as many as 16 and sometimes 20 intervening segments. However, the mean value of this rostrocaudal phase decreased with increasing number of blocked segments from the control value of approximately 1% per segment. By contrast, phase lags within the rostral and caudal end regions remained unaffected. The cycle frequency in the rostral and caudal regions decreased with the number of blocked middle segments and tended to diverge when a large number of middle segments was blocked. The variability in cycle frequency and intersegmental phase both increased with increasing number of blocked segments. In addition, a number of differences were noted in the properties of the motor output of the rostral and caudal regions of the spinal cord. The results indicate that the maximal functional length of propriospinal coupling fibers is at least 16-20 segments in I. unicuspis, whereas intersegmental phase lags are controlled at a local level and are not dependent on extended multisegmental coupling. Other possible roles for multisegmental coupling are discussed.

Dynamics of tremor-related oscillations in the human globus pallidus: a single case study.

Physiological evidence indicates that the resting tremor of Parkinson's disease originates in oscillatory neural activity in the forebrain, but it is unknown whether that activity is globally synchronized or consists of parallel, independently oscillating circuits. In the present study, we used dual microelectrodes to record tremor-related neuronal activity from eight sites in the internal segment of the globus pallidus (GPi) from an awake Parkinson's disease patient undergoing stereotaxic pallidotomy. We utilized spectral analysis to evaluate the temporal correlations between multiunit activity at spatially separated sites and between neural and limb electromyographic activity. We observed that some GPi neural pairs oscillated synchronously at the tremor frequency, whereas other neural pairs oscillated independently. Additionally, we found that GPi tremor-related activity at a given site could fluctuate between states of synchronization and independence with respect to upper limb tremor. Consistent with this finding, some paired recording sites within GPi showed periods of transient synchronization. These observations support the hypothesis of independent tremor-generating circuits whose coupling can fluctuate over time.

Spectral analysis of oscillatory neural circuits.

Oscillatory dynamics are found at all levels of the nervous system. The goal of our current research on the control of rhythmic motor output by the lamprey spinal cord is to determine the features of neuronal coupling that lead to stable oscillatory activity and precisely-controlled intersegmental phase. Since our experimental manipulations can greatly increase the variability of the ventral root bursting pattern, it is important for us to employ a data analysis method which remains valid independent of this variability. Traditional analysis approaches which rely on identification of burst event times do not generally satisfy this requirement. In this paper, we illustrate the application of a straightforward statistically-based method for determining important parameters of oscillatory motor circuits using Fourier spectral analysis of spike trains. The frequency, phase, and their variabilities can be quantified; and the relative strength of coupling between different parts of the circuit can be tested for statistical significance. The approach we adopt is highly convenient for neuroscientists who study oscillatory systems as it operates directly on trains of action potentials stored as lists of event times (point-processes). Basic concepts and practical issues concerning use of Fourier analysis are discussed.

Analysis and modeling of the locomotor central pattern generator as a network of coupled oscillators.

The primary functions of spinal locomotor central pattern generators (CPGs) are to provide oscillatory motor commands to individual joints or segments and to control the precise timing of those commands across all joints or segments for efficient, coordinated locomotor behavior. Our ability to understand the neuronal mechanisms underlying intersegmental coordination has been hampered by the complexity of propriospinal interconnectivity and the paucity of quantitative data on the magnitude and timing of those connections. Theoretical approaches have therefore been employed to discover general rules by which CPG-like oscillator systems must be constructed to produce appropriate coordinated locomotor behavior; the locomotor CPG is represented as a network of oscillators, where each oscillator generates local motor output and interoscillator coupling provides intersegmental coordination. Mathematical analysis of such coupled oscillator systems has provided a number of experimentally testable predictions regarding the link between coupling and coordination. Application of these network-level predictions to the results of electrophysiological experiments has required data analysis methods that can relate the behavior of the in vitro spinal cord to the variables employed by the mathematical model. Hence, our most recent work has focused on developing analytic tools for quantifying the changes in locomotor output that result form experimental manipulations of the propriospinal system in terms of frequency, intersegmental phase, and intersegmental correlation. Results of recent experiments can now be used to put further constraints on the allowable kinds of intersegmental coupling provided by mathematical modeling of the system.

Effects of local oscillator frequency on intersegmental coordination in the lamprey locomotor CPG: theory and experiment.

1. Experiments have been performed on in vitro preparations of lamprey spinal cord bathed in D-glutamate, which induces a pattern of activity recorded from ventral roots that is similar to that seen in the intact animal during swimming. The frequency of fictive swimming increases with increasing D-glutamate concentration, but intersegmental phase lag remains unaffected. 2. The effects on intersegmental phase lags of unequal activation of the rostral and caudal halves of a preparation were determined. Unequal activation was produced by placing a diffusion barrier in the middle of the chamber and perfusing the two halves with different concentrations of D-glutamate. 3. Within the rostral compartment, the phase lag increased from control when the rostral D-glutamate concentration was higher than the caudal concentration, and decreased from control when it was lower. By contrast, the phase lags within the caudal compartment did not depend on the ratio of D-glutamate concentration between the two compartments. 4. The frequency of the ventral root activity during differential activation was not significantly different from that of control experiments that had the same concentration as in the rostral compartment. 5. The results are discussed within the context of the mathematical analysis of chains of coupled oscillators by Kopell and Ermentrout and other current theories about the mechanisms of intersegmental coordination in the lamprey.

Interactions between muscle activation, body curvature and the water in the swimming lamprey.

The travelling wave of curvature which propels a fish forward arises from the interaction of the patterns of motoneurone activity generated by the spinal cord with the mechanical properties of (1) the muscle, (2) the skin, bone and connective tissues of the body, and (3) the water in which it is swimming. Furthermore, in the lamprey, a powerful feedback system has been demonstrated which allows local body curvature to influence the timing of the activity pattern generated by the spinal cord. The relative timing between activation and curvature are illustrated for both closed- and open-loop conditions, using data from intact swimming lampreys and from an in vitro preparation of lamprey spinal cord and notochord. The mechanical behaviour of a lamprey has been simulated with a mathematical model based on springs, dashpots, light rods, point masses and power units incorporating properties of lamprey muscle. Results are presented which illustrate the behaviour of a lamprey out of water. To anticipate the inclusion of the lamprey body model in the computation of the fluid dynamics, a hydrodynamical model has been developed in which the body motion and the forward swimming have been prescribed by mathematical functions. Results are presented to illustrate the hydrodynamic vortex structure as predicted by a two-dimensional, time-dependent numerical solution of the Navier-Stokes equations, including both viscous and inertial terms.

Intersegmental phase lags in the lamprey spinal cord: experimental confirmation of the existence of a boundary region.

A critical feature of the motor pattern generated by the lamprey spinal cord is an intersegmental delay that is constant down the cord and scales with cycle duration. This has been modelled as the output of a chain of coupled oscillators, within a general mathematical framework developed by Kopell and Ermentrout (1986, 1988). The analysis predicts that for asymmetric coupling of equally-activated oscillators, the intersegmental phase lag will be uniform along the chain except in a boundary layer at one end. Here we provide experimental evidence that a boundary layer does occur at the rostral end of an isolated preparation of lamprey spinal cord. In the context of the mathematical analysis, this indicates that ascending coupling is dominant in the control of intersegmental phase lag in the lamprey.

Modelling of intersegmental coordination in the lamprey central pattern generator for locomotion.

Rhythmic motor activity requires coordination of different muscles or muscle groups so that they are all active with the same cycle duration and appropriate phase relationships. The neural mechanisms for such phase coupling in vertebrate locomotion are not known. Swimming in the lamprey is accomplished by the generation of a travelling wave of body curvature in which the phase coupling between segments is so controlled as to give approximately one full wavelength on the body at any swimming speed. This article reviews work that has combined mathematical analysis, biological experimentation and computer simulation to provide a conceptual framework within which intersegmental coordination can be investigated. Evidence is provided to suggest that in the lamprey, ascending coupling is dominant over descending coupling and controls the intersegmental phase lag during locomotion. The significance of long-range intersegmental coupling is also discussed.

Forcing of coupled nonlinear oscillators: studies of intersegmental coordination in the lamprey locomotor central pattern generator.

1. This paper reports the results of an investigation of the basic mechanisms underlying intersegmental coordination in lamprey locomotion, by the use of a combined mathematical and biological approach. 2. Mathematically, the lamprey central pattern generator (CPG) is described as a chain of coupled nonlinear oscillators; experimentally, entrainment of fictive locomotion by imposed movement has been investigated. Interpretation of the results in the context of the theory has allowed conclusions to be drawn about the nature of ascending and descending coupling in the lamprey spinal CPG. 3. Theory predicts and data show that 1) the greater the number of oscillators in the chain, the smaller is the entrainment frequency range and 2) it is possible to entrain both above and below the rest frequency at one end but only above or below at the other end. 4. In the context of the experimental results, the theory indicates the following: 1) ascending coupling sets the intersegmental phase lags, whereas descending coupling changes the frequency of the coupled oscillators; 2) there are differences in the ascending and descending coupling other than strength; and it also suggests that 3) coupling slows down the oscillators.

Effects of bicuculline and strychnine on synaptic inputs to edge cells during fictive locomotion.

Edge cells are mechanoreceptive neurones located in the lateral tracts of the lamprey spinal cord. Phasic activation of these cells by lateral bending can entrain the activity of the locomotor central pattern generator. During fictive locomotion induced by bath-applied NMDLA (N-methyl-D,L-aspartate) or sensory stimulation, edge cells receive synaptic input. In this paper we provide evidence that the tonic inhibition received during sensory-induced fictive locomotion is glycinergic. We also show that during fictive locomotion induced by application of NMDLA to the spinal cord, bicuculline unveils phasic synaptic activity in edge cells. During sensory-evoked fictive locomotion, by contrast, only tonic synaptic activity is apparent in the presence of bicuculline.

GABAergic control of rhythmic activity in the presence of strychnine in the lamprey spinal cord.

Rhythmic ventral root activity has been induced in the spinal cord of the lamprey in vitro in the presence of strychnine. Bicuculline (a GABAA blocker) increases the initial frequency and decreases the episode duration of such activity, whereas diazepam (which potentiates GABA action) has the opposite effect. In addition, bicuculline slows the depolarisation of ventral horn neurones. However, voltage clamp at potentials positive to the interburst potential does not reveal net outward current, even in the presence of diazepam, indicating that the effects of GABA on the rhythmic activity must be presynaptic to the impaled cells.

Excitatory neurotransmission activates voltage-dependent properties in neurons in spinal motor system of lamprey.

1. Ventral horn neurons were studied under voltage clamp during episodes of sensory-evoked rhythmic coactivation in the in vitro lamprey spinal cord-tailfin preparation in the presence of strychnine. 2. Voltage clamp under a range of holding potentials during episodes of rhythmic coactivation revealed inward currents coincident with ventral root bursting in the same hemisegment and an apparent reversal potential of about -10 mV. 3. The current-voltage relationship of the peak inward current during each burst of this activity demonstrated a marked voltage dependency. 4. The voltage dependence of the inward current was eliminated by the specific NMDA-receptor blocker, APV, and by removal of Mg2+ from the bathing solution. 5. At depolarized potentials a long-lasting outward current could be observed, indicating an apparent voltage-dependent conductance for K+ and/or Cl-. This current was also blocked by APV and increased by the removal of Mg2+. 6. These results provide evidence that during rhythmic coactivation in strychnine, endogenous release of excitatory amino acid transmitter induces nonlinear conductance properties in ventral horn neurons by the activation of NMDA receptors. The results provide additional evidence that such activation contributes to the membrane potential oscillations that underlie rhythmic locomotory activity.

Features of entrainment of spinal pattern generators for locomotor activity in the lamprey spinal cord.

The in vitro lamprey spinal cord contains a "central pattern generator" (CPG) that can generate locomotor activity with excitatory amino acids added to the bath. The motor pattern can be entrained by imposed rhythmic bending of either the caudal or rostral end of the notochord/spinal cord. In the present study, the quantitative and mechanistic features of entrainment were investigated. Increasing the amplitude of the imposed movement increased the range of frequencies over which entrainment occurred. Brief, pulsed, imposed movements could reset the locomotor rhythm. During entrainment at different imposed movement frequencies, the burst duration was a constant proportion of about 35% of the cycle time. The intersegmental phase lag, which is usually constant at about 0.01 during locomotion, decreased significantly with caudal imposed movements. A small increase in the phase lags was observed with rostral imposed movements. In low-calcium Ringer's, briefly bending the notochord/spinal cord activated intraspinal mechanoreceptors and elicited ascending and descending unit activity in lateral spinal fascicles many segments from the point of bending. However, this ascending or descending movement-related activity was insufficient to fully entrain the locomotor rhythm, since blocking the pattern in the region of bending abolished 1:1 entrainment. The mechanoreceptors appear to act locally on the CPG networks, since interrupting the ascending or descending movement-related activity with lesions of the lateral fascicles did not abolish entrainment. In contrast, stripping the very lateral margins of the spinal cord in the region of bending did abolish entrainment, presumably by destroying the transduction region of the mechanoreceptors. The data, taken together, suggest that the mechanoreceptors entrain the local CPG networks, and this timing information is then distributed to the other parts of the spinal motor networks through the coordinating system.

The bag cells of Aplysia as a multitransmitter system: identification of alpha bag cell peptide as a second neurotransmitter.

The bag cell neurons of the marine mollusk, Aplysia, are a putative multitransmitter system that utilizes two or more peptide transmitters derived from a common precursor protein. Two putative transmitters are egg-laying hormone (ELH), a 36 amino acid peptide that induces egg laying and mediates bag cell-induced excitatory effects on certain abdominal ganglion neurons, and alpha-bag cell peptide (alpha BCP), which mimics bag cell-induced inhibition of the left upper quadrant (LUQ) neurons and the depolarization of the bag cells that occurs during the bag cell burst discharge. Alpha BCP was previously purified from bag cell extracts in three neuroactive forms: alpha BCP(1-9), a nine amino acid peptide encoded on the ELH/BCP precursor protein, and two NH2-terminal fragments, alpha BCP(1-8) and alpha BCP(1-7). Analyzing bag cell-induced inhibition of LUQ neurons, we report here that alpha BCP fulfills the main criteria for transmitter identification: stimulation of individual bag cells produces inhibition of the neurons; inhibitory activity is present in releasate collected following an elicited bag cell burst discharge in the presence of protease inhibitors; alpha BCP(1-9) and alpha BCP(1-8) are detected in the releasate in the presence of protease inhibitors; alpha BCP is rapidly inactivated after release, as indicated by the lack of detectable alpha BCP or inhibitory activity in the releasate in the absence of protease inhibitors, and by the increase in potency of the arterially perfused peptide in the presence of protease inhibitors; alpha BCP and the endogenously released transmitter produce apparently identical changes in membrane conductance; bag cell-induced inhibition is reduced or abolished following desensitization of the inhibitory response by long-term application of high concentrations of alpha BCP. The results provide additional evidence that the bag cells are a multitransmitter system and also suggest that many of the physiological properties of alpha BCP-mediated neurotransmission differ from those of ELH. First, unlike ELH, alpha BCP is rapidly inactivated after release. Second, alpha BCP(1-9) may be activated by carboxypeptidase cleavage since alpha BCP(1-8) and alpha BCP(1-7) are 30 and 10X as potent, respectively, as alpha BCP(1-9). Third, the inhibitory action of alpha BCP on its targets has a more rapid onset and a shorter time course than the excitatory actions of ELH. Thus, alpha BCP may diffuse to less distant targets than ELH and serve to regulate the more rapidly occurring neural events underlying egg-laying behavior.

Identification and primary structural analysis of peptide II, an end-product of precursor processing in cells R3-R14 of Aplysia.

Peptide II, which is encoded on a gene for a precursor protein in abdominal ganglion neurons R3-R14, was purified from extracts of abdominal ganglia of Aplysia californica. Native peptide II comigrates with synthetic standards on HPLC under isocratic conditions. Amino acid sequence and composition analyses indicate that the sequence of peptide II is Glu-Ala-Glu-Glu-Pro-Ser-Phe-Met-Thr-Arg-Leu, as predicted from the precursor. The molluscan cardioexcitatory peptide Phe-Met-Arg-Phe-amide was also identified in abdominal ganglion extracts by similar means. The large amount of peptide II recovered (100 ng/ganglion), and its location on the precursor between two pairs of basic residues, strongly suggest that the precursor is processed into peptide II and at least two other peptides. Although cells R3-R11 have been postulated to play a role in cardiovascular control, peptide II was without effect at less than or equal to 10(-4) M concentrations on identified abdominal ganglion neurons, the gastroesophageal artery or the heart. The physiological role of peptide II therefore remains to be elucidated.

Activation of NMDA receptors elicits fictive locomotion and bistable membrane properties in the lamprey spinal cord.

The motor pattern underlying locomotion in the lamprey can be elicited in the spinal cord in vitro by applying excitatory amino acids that activate NMDA receptors. When this is done oscillatory membrane potentials phase-linked with the locomotory rhythm can be recorded in different types of neurones. In some spinal neurones large amplitude oscillation continues after elimination of synaptic input with application of TTX. This oscillatory pacemaker-like activity is dependent on an activation of NMDA receptors, and is probably important in the generation of locomotion.

Sensory alteration of motor patterns in the stomatogastric nervous system of the spiny lobster Panulirus interruptus.

1. Stretching the pyloric region of the lobster's stomach in a manner that resembles pyloric dilation triggers a prolonged burst of impulses in two interneurones with axons in the inferior ventricular nerve (IVN). The burst is activated in the oesophageal ganglion by sensory axons that traverse the lateral ventricular nerves, the dorsal ventricular nerve and the stomatogastric nerve. These sensory axons do not appear to make synaptic contacts in the stomatogastric ganglion. 2. Electrical stimulation of sensory branches of the pyloric nerve triggers similar bursts in the IVN interneurones. 3. The burst of impulses in the IVN interneurones lasts from 2 to 30 s and the impulse frequency ranges from 10 to 80 Hz in different parts of the burst. Once triggered, burst structure and burst duration are independent of the intensity or duration of stimuli applied to the sensory nerves. 4. These bursts alter both the gastric and pyloric motor patterns. The IVN interneurones make a complex pattern of synapses with stomatogastric neurones. These are: pyloric dilators (PD) - excitation and slow inhibition; ventricular dilator (VD) - excitation; gastric mill (GM) neurones - inhibition; lateral posterior gastric neurones (LPGN) - inhibition; and Interneurone I (Int I) - excitation and slow inhibition. The size of the p.s.p.s at each of these synapses depends on the duration and impulse-frequency of the burst in the presynaptic neurones, which in turn alters the firing patterns of the stomatogastric neurones in various ways.