Technology Insight: future neuroprosthetic therapies for disorders of the nervous system

Richard A Normann
Nature Clinical Practice Neurology (2007) 3, 444-452 doi:10.1038/ncpneuro0556

Most disorders of the nervous system result from localized sensory or motor pathologies attributable to disease or trauma. The emerging field of neuroprosthetics is focused on the development of therapeutic interventions that will be able to restore some of this lost neural function by selective electrical stimulation of sensory or motor pathways, or by harnessing activity recorded from remnant neural pathways. A key element in this restoration of function has been the development of a new generation of penetrating microelectrode arrays that provide unprecedented selective access to the neurons of the CNS and PNS. The active tips of these microelectrode arrays penetrate the nervous tissues and abut against small populations of neurons or nerve fibers, thereby providing selective access to these cells. These electrode arrays are not only beginning to provide researchers with the ability to better study the spatiotemporal information processing performed by the nervous system, they can also form the basis for new therapies for disorders of the nervous system. In this Review, three examples of this new generation of microelectrode arrays are described, as are potential therapeutic applications in blindness and spinal cord injury, and for the control of prosthetic limbs.

Free full text: http://www.nature.com/ncpneuro/journal/v3/n8/pdf/ncpneuro0556.pdf

Behavioural improvements with thalamic stimulation

N. D. Schiff, J. T. Giacino, K. Kalmar, J. D. Victor, K. Baker, M. Gerber, B. Fritz, B. Eisenberg, J. O’Connor, E. J. Kobylarz, S. Farris, A. Machado, C. McCagg, F. Plum, J. J. Fins, A. R. Rezai
Nature 448, 600-603(2 August 2007) doi:10.1038/nature06041

Widespread loss of cerebral connectivity is assumed to underlie
the failure of brain mechanisms that support communication and
goal-directed behaviour following severe traumatic brain injury.
Disorders of consciousness that persist for longer than 12 months
after severe traumatic brain injury are generally considered to be
immutable; no treatment has been shown to accelerate recovery or
improve functional outcome in such cases1,2. Recent studies have
shown unexpected preservation of large-scale cerebral networks in
patients in the minimally conscious state (MCS)3,4, a condition
that is characterized by intermittent evidence of awareness of self
or the environment5. These findings indicate that there might be
residual functional capacity in some patients that could be supported
by therapeutic interventions. We hypothesize that further
recovery in some patients in the MCS is limited by chronic underactivation
of potentially recruitable large-scale networks. Here, in
a 6-month double-blind alternating crossover study, we show that
bilateral deep brain electrical stimulation (DBS) of the central
thalamus modulates behavioural responsiveness in a patient
who remained in MCS for 6 yr following traumatic brain injury
before the intervention. The frequency of specific cognitively
mediated behaviours (primary outcome measures) and functional
limb control and oral feeding (secondary outcome measures)
increased during periods in which DBS was on as compared with
periods in which it was off. Logistic regression modelling shows a
statistical linkage between the observed functional improvements
and recent stimulation history. We interpret the DBS effects as
compensating for a loss of arousal regulation that is normally
controlled by the frontal lobe in the intact brain. These findings
provide evidence that DBS can promote significant late functional
recovery from severe traumatic brain injury. Our observations,
years after the injury occurred, challenge the existing practice of
early treatment discontinuation for patients with only inconsistent
interactive behaviours and motivate further research to
develop therapeutic interventions.

PMID: 17671503
Fulltext: http://www.nature.com/nature/journal/v448/n7153/full/448539a.html

Abnormal FMRI adaptation to unfamiliar faces in a case of developmental prosopamnesia

Williams MA, Berberovic N, Mattingley JB
Curr Biol. 2007 Jul 17;17(14):1259-64

In rare cases, damage to the temporal lobe causes a selective impairment in the ability to learn new faces, a condition known as prosopamnesia [1]. Here we present the case of an individual with prosopamnesia in the absence of any acquired structural lesion. "C" shows intact processing of simple and complex nonface objects, but her ability to learn new faces is severely impaired. We used a neural marker of perceptual learning known as repetition suppression to examine functioning within C's fusiform face area (FFA), a region of cortex involved in face perception [2]. For comparison, we examined repetition suppression in the scene-selective parahippocampal place area (PPA) [3]. As expected, normal controls showed significant region-specific attenuation of neural activity across repetitions of each stimulus class. C also showed normal attenuation within the PPA to familiar and unfamiliar scenes, and within the FFA to familiar faces. Critically, however, she failed to show any adaptive change within the FFA for repeated unfamiliar faces, despite a face-specific blood-oxygen-dependent response (BOLD) response in her FFA during viewing of face stimuli. Our findings suggest that in developmental prosopamnesia, the FFA cannot maintain stable representations of new faces for subsequent recall or recognition.

PMID: 17614283

Fulltext: http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6VRT-4P48D06-8-B&_cdi=6243&_user=10&_orig=search&_coverDate=07%2F17%2F2007&_sk=999829985&view=c&wchp=dGLbVtz-zSkWb&md5=77db69cb4705be2249a6b7f4aeaca0a0&ie=/sdarticle.pdf

Statistics of Midbrain Dopamine Neuron Spike Trains in the Awake Primate

Bayer HM, Lau B, Glimcher PW
J Neurophysiol. 2007 Jul 5;

Work in behaving primates indicates that midbrain dopamine neurons encode a prediction error, the difference between an obtained reward and the reward expected. Studies of dopamine action potential timing in the alert and anaesthetized rat indicate that dopamine neurons respond in tonic and phasic modes, a distinction that has been less well characterized in the primates. We used spike train models to examine the relationship between the tonic and burst modes of activity in dopamine neurons while monkeys were performing a reinforced visuo-saccadic movement task. We studied spiking activity during four task-related intervals; two of these were intervals during which no task-related events occurred, while two were periods marked by task-related phasic activity. We found that dopamine neuron spike trains during the intervals when no events occurred were well described as tonic. Action potentials appeared to be independent, to occur at low frequency, and to be almost equally well described by Gaussian and Poisson-like (Gamma) processes. Unlike in the rat, interspike intervals as low as 20 ms were often observed during these presumptively tonic epochs. Having identified these periods of presumptively tonic activity we were able to quantitatively define phasic modulations (both increases and decreases in activity) during the intervals in which task-related events occurred. This analysis revealed that the phasic modulations of these neurons include both bursting, as has been described previously, and pausing. Together bursts and pauses seemed to provide a continuous, although non-linear, representation of the theoretically defined reward prediction error of reinforcement learning.

PMID: 17615124

Fulltext: http://jn.physiology.org/cgi/reprint/01140.2006v1

Individuation and holistic processing of faces in rhesus monkeys

Dahl CD, Logothetis NK, Hoffman KL
Proc Biol Sci. 2007 Sep 7;274(1622):2069-76

Despite considerable evidence that neural activity in monkeys reflects various aspects of face perception, relatively little is known about monkeys' face processing abilities. Two characteristics of face processing observed in humans are a subordinate-level entry point, here, the default recognition of faces at the subordinate, rather than basic, level of categorization, and holistic effects, i.e. perception of facial displays as an integrated whole. The present study used an adaptation paradigm to test whether untrained rhesus macaques (Macaca mulatta) display these hallmarks of face processing. In experiments 1 and 2, macaques showed greater rebound from adaptation to conspecific faces than to other animals at the individual or subordinate level. In experiment 3, exchanging only the bottom half of a monkey face produced greater rebound in aligned than in misaligned composites, indicating that for normal, aligned faces, the new bottom half may have influenced the perception of the whole face. Scan path analysis supported this assertion: during rebound, fixation to the unchanged eye region was renewed, but only for aligned stimuli. These experiments show that macaques naturally display the distinguishing characteristics of face processing seen in humans and provide the first clear demonstration that holistic information guides scan paths for conspecific faces.

PMID: 17609192

Free Fulltext: http://www.journals.royalsoc.ac.uk/content/9w71833h18243416/

The Neural Basis of Decision Making

Gold JI, Shadlen MN
Annu Rev Neurosci. 2007 Jul 21;30:535-574

The study of decision making spans such varied fields as neuroscience, psychology, economics, statistics, political science, and computer science. Despite this diversity of applications, most decisions share common elements including deliberation and commitment. Here we evaluate recent progress in understanding how these basic elements of decision formation are implemented in the brain. We focus on simple decisions that can be studied in the laboratory but emphasize general principles likely to extend to other settings.

PMID: 17600525

Fulltext: http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.neuro.29.051605.113038

Multiple dopamine functions at different time courses

Schultz W
Annu Rev Neurosci. 2007;30:259-88

Many lesion studies report an amazing variety of deficits in behavioral functions that cannot possibly be encoded in great detail by the relatively small number of midbrain dopamine neurons. Although hoping to unravel a single dopamine function underlying these phenomena, electrophysiological and neurochemical studies still give a confusing, mutually exclusive, and partly contradictory account of dopamine's role in behavior. However, the speed of observed phasic dopamine changes varies several thousand fold, which offers a means to differentiate the behavioral relationships according to their time courses. Thus dopamine is involved in mediating the reactivity of the organism to the environment at different time scales, from fast impulse responses related to reward via slower changes with uncertainty, punishment, and possibly movement to the tonic enabling of postsynaptic motor, cognitive, and motivational systems deficient in Parkinson's disease.

PMID: 17600522

Fulltext: http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.neuro.28.061604.135722

A Model of V4 Shape Selectivity and Invariance

Cadieu C, Kouh M, Pasupathy A, Connor C, Riesenhuber M, Poggio TA
J Neurophysiol. 2007 Jun 27;

Object recognition in primates is mediated by the ventral visual pathway and is classically described as a feedforward hierarchy of increasingly sophisticated representations. Neurons in macaque monkey area V4, an intermediate stage along the ventral pathway, have been shown to exhibit selectivity to complex boundary conformation and invariance to spatial translation. How could such a representation be derived from the signals in lower visual areas such as V1? We show that a quantitative model of hierarchical processing, which is part of a larger model of object recognition in the ventral pathway, provides a plausible mechanism for the translation-invariant shape representation observed in area V4. Simulated model neurons successfully reproduce V4 selectivity and invariance through a nonlinear, translation-invariant combination of locally selective subunits, suggesting that a similar transformation may occur or culminate in area V4. Specifically, this mechanism models the selectivity of individual V4 neurons to boundary conformation stimuli, exhibits the same degree of translation invariance observed in V4, and produces observed V4 population responses to bars and non-Cartesian gratings. This work provides a quantitative model of the widely described shape selectivity and invariance properties of area V4 and points toward a possible canonical mechanism operating throughout the ventral pathway.

PMID: 17596412

Fulltext: http://jn.physiology.org/cgi/reprint/01265.2006v1

Quantitative comparison between neural response in macaque inferotemporal cortex and behavioral discrimination of photographic images

Allred SR, Jagadeesh B
J Neurophysiol. 2007 Jun 27;

Inferotemporal (IT) cortex plays a critical role in the primate ability to perceive and discriminate between images, but the relationship between responses of single neurons and behavioral capacities is poorly understood. We studied this relationship by recording from IT neurons while monkeys performed a delayed-match-to-sample task with two images. On each day, two sample images were chosen to maximize the selectivity of the neuron, and task difficulty was manipulated by varying sample duration and by masking the sample. On each trial, monkeys reported which of the two sample images was presented. Neural performance was described using an ideal observer analysis. Across the population, neural and behavioral sensitivity to changes in sample duration were indistinguishable. Neural sensitivity was dependent on epoch used to analyze neural response; maximal neural sensitivity was achieved in the 128 ms epoch that began 85 ms after sample onset. At most sample durations, the epoch that yielded optimal neural performance was longer than the sample duration, suggesting that neural selectivity persisted after the presentation of the mask during performance of the task. A control experiment showed that neural and behavioral performance improved in the absence of the mask. These observations suggest that the responses of individual IT neurons contain sufficient information to allow behavioral discrimination of images in a demanding task.

PMID: 17596424

Modulation of neuronal interactions through neuronal synchronization

Womelsdorf T, Schoffelen JM, Oostenveld R, Singer W, Desimone R, Engel AK, Fries P
Science. 2007 Jun 15;316(5831):1609-12

Brain processing depends on the interactions between neuronal groups. Those interactions are governed by the pattern of anatomical connections and by yet unknown mechanisms that modulate the effective strength of a given connection. We found that the mutual influence among neuronal groups depends on the phase relation between rhythmic activities within the groups. Phase relations supporting interactions between the groups preceded those interactions by a few milliseconds, consistent with a mechanistic role. These effects were specific in time, frequency, and space, and we therefore propose that the pattern of synchronization flexibly determines the pattern of neuronal interactions.

PMID: 17569862
Fulltext: http://www.sciencemag.org/cgi/content/full/316/5831/1609