Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.

There are two views as to the character of basal-ganglia processing - processing by segregated parallel circuits or by information sharing. To distinguish between these views, we studied the simultaneous activity of neurons in the output stage of the basal ganglia with cross-correlation techniques. The firing of neurons in the globus pallidus of normal monkeys is almost always uncorrelated. However, after dopamine depletion and induction of parkinsonism by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), oscillatory activity appeared and the firing of many neurons became correlated. We conclude that the normal dopaminergic system supports segregation of the functional subcircuits of the basal ganglia, and that a breakdown of this independent processing is a hallmark of Parkinson's disease.

Long-term optical imaging and spectroscopy reveal mechanisms underlying the intrinsic signal and stability of cortical maps in V1 of behaving monkeys.

Explorations of learning and memory, other long-term plastic changes, and additional cognitive functions in the behaving primate brain would greatly benefit from the ability to image the functional architecture within the same patch of cortex, at the columnar level, for a long period of time. We developed methods for long-term optical imaging based on intrinsic signals and repeatedly visualized the same functional domains in behaving macaque cortex for a period extending over 1 year. Using optical imaging and imaging spectroscopy, we first explored the relationship between electrical activity and hemodynamic events in the awake behaving primate and compared it with anesthetized preparations. We found that, whereas the amplitude of the intrinsic signal was much larger in the awake animal, its temporal pattern was similar to that observed in the anesthetized animals. In both groups, deoxyhemoglobin concentration reached a peak 2-3 sec after stimulus onset. Furthermore, the early activity-dependent increase in deoxyhemoglobin concentration (the "initial dip") was far more tightly colocalized with electrical activity than the delayed increase in oxyhemoglobin concentration, known to be associated with an increase in blood flow. The implications of these results for improvement of the spatial resolution of blood oxygenation level-dependent functional magnetic resonance imaging are discussed. After the characterization of the intrinsic signal in the behaving primate, we used this new imaging method to explore the stability of cortical maps in the macaque primary visual cortex. Functional maps of orientation and ocular dominance columns were found to be stable for a period longer than 1 year.

Intraarticular iliotibial band reconstruction for anterior cruciate ligament insufficiency.

Intraarticular reconstruction of the anterior cruciate ligament by transferring the distal aspect and insertion of the iliotibial band has been clinically successful. Our surgical technique theoretically retains normal neurovascular supply, and thus, the potential for dynamic repair exists. Thirty-five patients, 28 men and 7 women, underwent this reconstruction. The average age was 24 years, with a range from 18 to 46. There were 27 chronic and 8 acute injuries. Pathological findings included an absent anterior cruciate (14 knees), severe stretching (13), failed reconstruction or repair (4), midportion tears (3), and avulsion (1). Postoperative patients were evaluated according to the Kennedy criteria. An anterior drawer of 2+ was not observed in any patient. There were no cases of 2+ rotary instability, and no pivot shifts. The possibility of a dynamic or proprioceptive repair was assessed by electromyography. While no evidence of electrical activity was recorded on the gluteus maximus on 60 normal knee examinations, all 10 tested postoperative iliotibial band patients had electrical activity. The failed results of the series showed no evidence of activity.

Neurons in the globus pallidus do not show correlated activity in the normal monkey, but phase-locked oscillations appear in the MPTP model of parkinsonism.

1. To test the mode of functional connectivity in the basal ganglia circuitry, we studied the activity of simultaneously recorded neurons in the globus pallidus (GP) of a behaving rhesus monkey. The cross-correlograms of pairs of neurons in the GP were compared with those of neurons in the thalamus and frontal cortex and to the cross-correlograms of pallidal pairs after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. 2. In contrast with cortical and thalamic neuronal activity, almost all pairs (n = 76/81 pairs; 93.8%, 1,629/1,651 histograms; 98.7%) of GP neurons in the normal monkey were not driven by a common input. 3. The monkey was systemically treated with MPTP until the appearance of parkinsonian signs and an intermittent 7- to 11-Hz action/postural tremor. After the MPTP treatment, many pallidal neurons (49/140; 35%) became oscillatory, and 19% (n = 31/162) of pallidal pairs had oscillatory cross-correlograms. 4. These results support the model of parallel processing in the basal ganglia of normal monkeys and suggest a breakdown of the independent activity in the parkinsonian state.

Spatiotemporal structure of cortical activity: properties and behavioral relevance.

The study was designed to reveal occurrences of precise firing sequences (PFSs) in cortical activity and to test their behavioral relevance. Two monkeys were trained to perform a delayed-response paradigm and to open puzzle boxes. Extracellular activity was recorded from neurons in premotor and prefrontal areas with an array of six microelectrodes. An algorithm was developed to detect PFSs, defined as a set of three spikes and two intervals with a precision of +/-1 ms repeating significantly more than expected by chance. The expected level of repetition was computed based on the firing rate and the pairwise correlation of the participating units, assuming a Poisson distribution of event counts. Accordingly, the search for PFSs was corrected for rate modulations. PFSs were found in 24/25 recording sessions. Most PFSs (76%) were composed of spikes of more than one unit but usually not more than two units (67%). The PFSs spanned hundreds of milliseconds, and the average interval between two events within the PFSs was 200 ms. No traces of periodic oscillations were found in the PFS intervals. The bins of the matrix that were defined as PFSs were isolated temporally: the spikes that generated PFSs were not associated with high-frequency bursts or rapid coherent rate fluctuations. A given PFS tended to be correlated with the animal's behavior. Furthermore, for 19% of the PFS pairs that shared the same unit composition, each member of the pair was associated with a different type of behavior. The PFSs often appeared in clusters that were associated with particular phases of the behavior. The firing rate of single units did not provide a full explanation for the timing and structure of these clusters. A reduced spike train (RST) was defined for each unit by taking all spikes of that unit that were part of any PFS. In 88% of the cases the degree of modulation of the RST was higher than that of the complete spike train. The results suggest that relevant information is carried by the fine temporal structure of cortical activity. A coding scheme that involves such temporal structures is rich and sufficiently flexible to facilitate a rapid organization of cortical neurons into functional groups. The results can be accounted for by the synfire chain model, which suggests that cortical activity is mediated by synchronous activation of neural groups in a reverberatory mode.

Dynamics of neuronal interactions in monkey cortex in relation to behavioural events.

It is possible that brain cortical function is mediated by dynamic modulation of coherent firing in groups of neurons. Indeed, a correlation of firing between cortical neurons, seen following sensory stimuli or during motor behaviour, has been described. However, the time course of modifications of correlation in relation to behaviour was not evaluated systematically. Here we show that correlated firing between single neurons, recorded simultaneously in the frontal cortex of monkeys performing a behavioural task, evolves within a fraction of a second, and in systematic relation to behavioural events. Moreover, the dynamic patterns of correlation depend on the distance between neurons, and can emerge even without modulation of the firing rates. These findings support the notion that neurons can associate rapidly into a functional group in order to perform a computational task, at the same time becoming dissociated from concurrently activated competing groups. Thus, they call for a revision of prevailing models of neural coding that rely solely on single neuron firing rates.

Frontal cognitive impairments and saccadic deficits in low-dose MPTP-treated monkeys.

There is considerable overlap between the cognitive deficits observed in humans with frontal lobe damage and those described in patients with Parkinson's disease. Similar frontal impairments have been found in the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) primate model of Parkinsonism. Here we provide quantitative documentation of the cognitive, oculomotor, and skeletomotor dysfunctions of monkeys trained on a frontal task and treated with low-doses (LD) of MPTP. Two rhesus monkeys were trained to perform a spatial delayed-response task with frequent alternations between two behavioral modes (GO and NO-GO). After control recordings, the monkeys were treated with one placebo and successive LD MPTP courses. Monkey C developed motor Parkinsonian signs after a fourth course of medium-dose (MD) MPTP and later was treated with combined dopaminergic therapy (CDoT). There were no gross motor changes after the LD MPTP courses, and the average movement time (MT) did not increase. However, reaction time (RT) increased significantly. Both RT and MT were further increased in the symptomatic state, under CDoT. Self-initiated saccades became hypometric after LD MPTP treatments and their frequency decreased. Visually triggered saccades were affected to a lesser extent by the LD MPTP treatments. All saccadic parameters declined further in the symptomatic state and improved partially during CDoT. The number of GO mode (no-response, location, and early release) errors increased after MPTP treatment. The monkeys made more perseverative errors while switching from the GO to the NO-GO mode. Saccadic eye movement patterns suggest that frontal deficits were involved in most observed errors. CDoT had a differential effect on the behavioral errors. It decreased omission errors but did not improve location errors or perseverative errors. Tyrosine hydroxylase immunohistochemistry showed moderate ( approximately 70-80%) reduction in the number of dopaminergic neurons in the substantia nigra pars compacta after MPTP treatment. These results show that cognitive and motor disorders can be dissociated in the LD MPTP model and that cognitive and oculomotor impairments develop before the onset of skeletal motor symptoms. The behavioral and saccadic deficits probably result from the marked reduction of dopaminergic neurons in the midbrain. We suggest that these behavioral changes result from modified neuronal activity in the frontal cortex.