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Major depressive disorder: mechanism-based prescribing for personalized medicine

Saltiel, Philip F; Silvershein, Daniel I
Individual patients with depression present with unique symptom clusters - before, during, and even after treatment. The prevalence of persistent, unresolved symptoms and their contribution to patient functioning and disease progression emphasize the importance of finding the right treatment choice at the onset and the utility of switching medications based on suboptimal responses. Our primary goal as clinicians is to improve patient function and quality of life. In fact, feelings of well-being and the return to premorbid levels of functioning are frequently rated by patients as being more important than symptom relief. However, functional improvements often lag behind resolution of mood, attributed in large part to persistent and functionally impairing symptoms - namely, fatigue, sleep/wake disturbance, and cognitive dysfunction. Thus, patient outcomes can be optimized by deconstructing each patient's depressive profile to its component symptoms and specifically targeting those domains that differentially limit patient function. This article will provide an evidence-based framework within which clinicians may tailor pharmacotherapy to patient symptomatology for improved treatment outcomes.
PMCID:4386790
PMID: 25848287
ISSN: 1176-6328
CID: 1528412

Combining modules for movement

Bizzi, E; Cheung, V C K; d'Avella, A; Saltiel, P; Tresch, M
We review experiments supporting the hypothesis that the vertebrate motor system produces movements by combining a small number of units of motor output. Using a variety of approaches such as microstimulation of the spinal cord, NMDA iontophoresis, and an examination of natural behaviors in intact and deafferented animals we have provided evidence for a modular organization of the spinal cord. A module is a functional unit in the spinal cord that generates a specific motor output by imposing a specific pattern of muscle activation. Such an organization might help to simplify the production of movements by reducing the degrees of freedom that need to be specified
PMCID:4295773
PMID: 18029291
ISSN: 1872-6321
CID: 99593

Modular organization of spinal motor systems

Bizzi, E; D'Avella, A; Saltiel, P; Tresch, M
The vertebrate nervous system produces a wide range of movement flexibly and efficiently, even though the simplest of these movements is potentially highly complex. The strategies by which the nervous system overcomes these complexities have therefore been of interest to motor physiologists for decades. In this review, the authors present a number of recent experiments that propose one strategy by which the nervous system might simplify the production of movement. These experiments suggest that spinal motor systems are organized in terms of a small number of distinct motor responses, or 'modules.' These distinct modules can be combined together simply to produce a wide range of different movements. Such a modular organization of spinal motor systems can potentially allow the nervous system to produce a wide range of natural behaviors in a simple and flexible manner
PMID: 12374428
ISSN: 1073-8584
CID: 99594

Muscle synergies encoded within the spinal cord: evidence from focal intraspinal NMDA iontophoresis in the frog

Saltiel, P; Wyler-Duda, K; D'Avella, A; Tresch, M C; Bizzi, E
This paper relates to the problem of the existence of muscle synergies, that is whether the CNS command to muscles is simplified by controlling their activity in subgroups or synergies, rather than individually. We approach this problem with two methods that have been recently introduced: intraspinal N-methyl-D-aspartate (NMDA) microstimulation and a synergy-extracting algorithm. To search for a common set of synergies encoded for by the spinal cord whose combinations would account for a large range of electromyographic (EMG) patterns, we chose, rather than examining a large range of natural behaviors, to chemically microstimulate a large number of spinal cord interneuronal sites in different frogs. A possible advantage of this complementary method is that it is task-independent. Visual inspection suggested that the NMDA-elicited EMG patterns recorded from 12 leg muscles might indeed be constructed from smaller subgroups of muscles whose activity co-varied, suggestive of synergies. We used a modification of our extracting computational algorithm whereby a nonnegative least-squares method was employed to iteratively update both the synergies and their coefficients of activation in reconstructing the EMG patterns. Using this algorithm, a limited set of seven synergies was found whose linear combinations accounted for more than 91% of the variance in the pooled EMG data from 10 frogs, and more than 96% in individual frogs. The extracted synergies were similar among frogs. Further, preferred combinations of these synergies were clearly identified. This was found by extracting smaller sets of four, five, or six synergies and fitting each synergy from those sets as a combination from the set of seven synergies extracted from the same frog; the synergy combinations from each frog were then pooled together to examine their frequency of occurrence. Concordance with this method of identifying synergy combinations was found by examining how the synergies from the set of seven correlated pair-wise as they reconstructed the EMG data. These results support the existence of muscle synergies encoded within the spinal cord, which through preferred combinations, account for a large repertoire of spinal cord motor output. These findings are contrasted with previous approaches to the problem of synergies
PMID: 11160497
ISSN: 0022-3077
CID: 99596

New perspectives on spinal motor systems

Bizzi, E; Tresch, M C; Saltiel, P; d'Avella, A
The production and control of complex motor functions are usually attributed to central brain structures such as cortex, basal ganglia and cerebellum. In traditional schemes the spinal cord is assigned a subservient function during the production of movement, playing a predominantly passive role by relaying the commands dictated to it by supraspinal systems. This review challenges this idea by presenting evidence that the spinal motor system is an active participant in several aspects of the production of movement, contributing to functions normally ascribed to 'higher' brain regions
PMID: 11252772
ISSN: 1471-003x
CID: 99595

Output units of motor behavior: an experimental and modeling study

Loeb, E P; Giszter, S F; Saltiel, P; Bizzi, E; Mussa-Ivaldi, F A
Cognitive approaches to motor control typically concern sequences of discrete actions without taking into account the stunning complexity of the geometry and dynamics of the muscles. This begs the question: Does the brain convert the intricate, continuous-time dynamics of the muscles into simpler discrete units of actions, and if so, how? One way for the brain to form discrete units of behavior from muscles is through the synergistic co-activation of muscles. While this possibility has long been known, the composition of potential muscle synergies has remained elusive. In this paper, we have focused on a method that allowed us to examine and compare the limb stabilization properties of all possible muscle combinations. We found that a small set (as few as 23 out of 65,536) of all possible combinations of 16 limb muscles are robust with respect to activation noise: these muscle combinations could stabilize the limb at predictable, restricted portions of the workspace in spite of broad variations in the force output of their component muscles. The locations at which the robust synergies stabilize the limb are not uniformly distributed throughout the leg's workspace, but rather, they cluster at four workspace areas. The simulated robust synergies are similar to the actual synergies we have previously found to be generated by activation of the spinal cord. Thus, we have developed a new analytical method that enabled us to select a few muscle synergies with interesting properties out of the set of possible muscle combinations. Beyond this, the identification of robustness as a common property of the synergies in simple motor behaviors will open the way to the study of dynamic stability, which is an important and distinct property of the vertebrate motor-control system
PMID: 10769307
ISSN: 0898-929x
CID: 99597

The construction of movement by the spinal cord

Tresch, M C; Saltiel, P; Bizzi, E
We used a computational analysis to identify the basic elements with which the vertebrate spinal cord constructs one complex behavior. This analysis extracted a small set of muscle synergies from the range of muscle activations generated by cutaneous stimulation of the frog hindlimb. The flexible combination of these synergies was able to account for the large number of different motor patterns produced by different animals. These results therefore demonstrate one strategy used by the vertebrate nervous system to produce movement in a computationally simple manner
PMID: 10195201
ISSN: 1097-6256
CID: 99598

Spinal cord modular organization and rhythm generation: an NMDA iontophoretic study in the frog

Saltiel, P; Tresch, M C; Bizzi, E
Previous work using electrical microstimulation has suggested the existence of modules subserving limb posture in the spinal cord. In this study, the question of modular organization was reinvestigated with the more selective method of chemical microstimulation. N-methyl--aspartate (NMDA) iontophoresis was applied to 229 sites of the lumbar spinal cord gray while monitoring the isometric force output of the ipsilateral hindlimb at the ankle. A force response was elicited from 69 sites. At 18 of these sites, tonic forces were generated and rhythmic forces at 44. In the case of tonic forces, their directions clustered along four orientations: lateral extension, rostral flexion, adduction, and caudal extension. For the entire set of forces (tonic and rhythmic), the same clusters of orientations were found with the addition of a cluster directed as a flexion toward the body. This distribution of force orientations was quite comparable to that obtained with electrical stimulation at the same sites. The map of tonic responses revealed a topographic organization; each type of force orientation was elicited from sites that grouped together in zones at distinct rostrocaudal and depth locations. In the case of rhythmic sequences of force orientations, some were distinctly more common, whereas others were rarely elicited by NMDA. Mapping of the most common rhythms showed that each was elicited from two or three regions of the cord. These regions were close in location to the tonic regions that produced those forces that represented components specific to that rhythm. There was an additional caudal region from which the different rhythms also could be elicited. Taken together, these results support the concept of a modular organization of the motor system in the frog's spinal cord and delineate the topography of these modules. They also suggest that these modules are used by the circuitry underlying rhythmic pattern generation by the spinal cord
PMID: 9819246
ISSN: 0022-3077
CID: 99599

Modular organization of motor behavior

Bizzi, E; Saltiel, P; Tresch, M
The issue of translating the planning of arm movements into muscle forces is discussed in relation to the recent discovery of structures in the spinal cord. These structures contain circuitry that, when activated, produce precisely balanced contractions in groups of muscles. These synergistic contractions generate forces that direct the limb toward an equilibrium point in space. Remarkably, the force outputs, produced by activating different spinal-cord structures, sum vectorially. This vectorial combination of motor outputs might be a mechanism for producing a vast repertoire of motor behaviors in a simple manner
PMID: 9755510
ISSN: 0939-5075
CID: 99600

Modular organization of motor behavior in the frog's spinal cord

Bizzi, E; Giszter, S F; Loeb, E; Mussa-Ivaldi, F A; Saltiel, P
The complex issue of translating the planning of arm movements into muscle forces is discussed in relation to the recent discovery of structures in the spinal cord. These structures contain circuitry that, when activated, produce precisely balanced contractions in groups of muscles. These synergistic contractions generate forces that direct the limb toward an equilibrium point in space. Remarkably, the force outputs, produced by activating different spinal-cord structures, sum vectorially. This vectorial combination of motor outputs might be a mechanism for producing a vast repertoire of motor behaviors in a simple manner
PMID: 8545910
ISSN: 0166-2236
CID: 99601