Aeyal Raz

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 Parkinsons disease.

Firing Patterns and Correlations of Spontaneous Discharge of Pallidal Neurons in the Normal and the Tremulous 1-Methyl-4- Phenyl-1,2,3,6-Tetrahydropyridine Vervet Model of Parkinsonism

To investigate the role of the basal ganglia in parkinsonian tremor, we recorded hand tremor and simultaneous activity of several neurons in the external and internal segments of the globus pallidus (GPe and GPi) in two vervet monkeys, before and after systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and development of parkinsonism with tremor of 5 and 11 Hz. In healthy monkeys, only 11% (20/174) of the GPe cells and 3% (1/29) of the GPi cells displayed significant 3–19 Hz oscillations. After MPTP treatment, 39% (107/271) of the GPe cells and 43% (26/61) of the GPi cells developed significant oscillations. Oscillation frequencies of single cells after MPTP treatment were bimodally distributed around 7 and 13 Hz. For 10% of the oscillatory cells that were recorded during tremor periods, there was a significant tendency for the tremor and neuronal oscillations to appear simultaneously. Cross-correlation analysis revealed a very low level of correlated activity between pallidal neurons in the normal state; 95.6% (477/499) of the pairs were not correlated, and oscillatory cross-correlograms were found in only 1% (5/499) of the pairs. After MPTP treatment, the correlations increased dramatically, and 40% (432/1080) of the cross-correlograms had significant oscillations, centered around 13–14 Hz. Phase shifts of the cross-correlograms of GPe pairs, but not of GPi, were clustered around 0°. The results illustrate that MPTP treatment changes the pattern of activity and synchronization in the GPe and GPi. These changes are related to the symptoms of Parkinsons disease and especially to the parkinsonian tremor.

Basal ganglia oscillations and pathophysiology of movement disorders

Low frequency rest tremor is one of the cardinal signs of Parkinsons disease and some of its animal models. Current physiological studies and models of the basal ganglia differ as to which aspects of neuronal activity are crucial to the pathophysiology of Parkinsons disease. There is evidence that neural oscillations and synchronization play a central role in the generation of the disease. However, parkinsonian tremor is not strictly correlated with the synchronous oscillations in the basal ganglia networks. Rather, abnormal basal ganglia output enforces abnormal thalamo-cortical processing leading to akinesia, the main negative symptom of Parkinsons disease. Parkinsonian tremor has probably evolved as a downstream compensatory mechanism.

Propofol decreases neuronal population spiking activity in the subthalamic nucleus of Parkinsonian patients.

BACKGROUND: Implantation of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN) for the treatment of Parkinson disease is often performed using microelectrode recording (MER) of STN population spike activity. The extent to which sedative drugs interfere with MER is unknown. We recorded the population activity of STN neurons during propofol sedation and examined its effect on neuronal activity. METHODS: The procedure was performed during DBS surgery for Parkinson disease. We administered propofol (50 &mgr;g/kg/min) at a constant electrode location in the STN until stable sedation was achieved. We recorded the electrical activity, and calculated its root mean square (RMS) before, during, and after the propofol infusions. RESULTS: The activity of 24 electrode trajectories was recorded in 16 patients. The RMS of STN activity decreased significantly after propofol administration in 18 of the 24 trajectories. The average normalized RMS decreased by 23.2%± 9.1% (mean ± SD) during propofol administration (P < 0.001), and returned to baseline 9.3 ± 4.0 minutes after it was stopped. CONCLUSIONS: Propofol administration leads to a significant decrease of STN neuronal activity. Thus, it may interfere with MER identification of the STN borders. However, activity returns to baseline shortly after administration stops. Therefore, propofol can be safely used until shortly before MER for DBS.

Incidence of Connected Consciousness after Tracheal Intubation: A Prospective, International, Multicenter Cohort Study of the Isolated Forearm Technique.

Background: The isolated forearm technique allows assessment of consciousness of the external world (connected consciousness) through a verbal command to move the hand (of a tourniquet-isolated arm) during intended general anesthesia. Previous isolated forearm technique data suggest that the incidence of connected consciousness may approach 37% after a noxious stimulus. The authors conducted an international, multicenter, pragmatic study to establish the incidence of isolated forearm technique responsiveness after intubation in routine practice. Methods: Two hundred sixty adult patients were recruited at six sites into a prospective cohort study of the isolated forearm technique after intubation. Demographic, anesthetic, and intubation data, plus postoperative questionnaires, were collected. Univariate statistics, followed by bivariate logistic regression models for age plus variable, were conducted. Results: The incidence of isolated forearm technique responsiveness after intubation was 4.6% (12/260); 5 of 12 responders reported pain through a second hand squeeze. Responders were younger than nonresponders (39 ± 17 vs. 51 ± 16 yr old; P = 0.01) with more frequent signs of sympathetic activation (50% vs. 2.4%; P = 0.03). No participant had explicit recall of intraoperative events when questioned after surgery (n = 253). Across groups, depth of anesthesia monitoring values showed a wide range; however, values were higher for responders before (54 ± 20 vs. 42 ± 14; P = 0.02) and after (52 ± 16 vs. 43 ± 16; P = 0.02) intubation. In patients not receiving total intravenous anesthesia, exposure to volatile anesthetics before intubation reduced the odds of responding (odds ratio, 0.2 [0.1 to 0.8]; P = 0.02) after adjustment for age. Conclusions: Intraoperative connected consciousness occurred frequently, although the rate is up to 10-times lower than anticipated. This should be considered a conservative estimate of intraoperative connected consciousness.

Preferential effect of isoflurane on top-down vs. bottom-up pathways in sensory cortex

The mechanism of loss of consciousness (LOC) under anesthesia is unknown. Because consciousness depends on activity in the cortico-thalamic network, anesthetic actions on this network are likely critical for LOC. Competing theories stress the importance of anesthetic actions on bottom-up “core” thalamo-cortical (TC) vs. top-down cortico-cortical (CC) and matrix TC connections. We tested these models using laminar recordings in rat auditory cortex in vivo and murine brain slices. We selectively activated bottom-up vs. top-down afferent pathways using sensory stimuli in vivo and electrical stimulation in brain slices, and compared effects of isoflurane on responses evoked via the two pathways. Auditory stimuli in vivo and core TC afferent stimulation in brain slices evoked short latency current sinks in middle layers, consistent with activation of core TC afferents. By contrast, visual stimuli in vivo and stimulation of CC and matrix TC afferents in brain slices evoked responses mainly in superficial and deep layers, consistent with projection patterns of top-down afferents that carry visual information to auditory cortex. Responses to auditory stimuli in vivo and core TC afferents in brain slices were significantly less affected by isoflurane compared to responses triggered by visual stimuli in vivo and CC/matrix TC afferents in slices. At a just-hypnotic dose in vivo, auditory responses were enhanced by isoflurane, whereas visual responses were dramatically reduced. At a comparable concentration in slices, isoflurane suppressed both core TC and CC/matrix TC responses, but the effect on the latter responses was far greater than on core TC responses, indicating that at least part of the differential effects observed in vivo were due to local actions of isoflurane in auditory cortex. These data support a model in which disruption of top-down connectivity contributes to anesthesia-induced LOC, and have implications for understanding the neural basis of consciousness.

Subthalamic nucleus long-range synchronization—an independent hallmark of human Parkinson's disease

Beta-band synchronous oscillations in the dorsolateral region of the subthalamic nucleus (STN) of human patients with Parkinsons disease (PD) have been frequently reported. However, the correlation between STN oscillations and synchronization has not been thoroughly explored. The simultaneous recordings of 2390 multi-unit pairs recorded by two parallel microelectrodes (separated by fixed distance of 2 mm, n = 72 trajectories with two electrode tracks >4 mm STN span) in 57 PD patients undergoing STN deep brain stimulation surgery were analyzed. Automatic procedures were utilized to divide the STN into dorsolateral oscillatory and ventromedial non-oscillatory regions, and to quantify the intensity of STN oscillations and synchronicity. Finally, the synchronicity of simultaneously vs. non-simultaneously recorded pairs were compared using a shuffling procedure. Synchronization was observed predominately in the beta range and only between multi-unit pairs in the dorsolateral oscillatory region (n = 615). In paired recordings between sites in the dorsolateral and ventromedial (n = 548) and ventromedial-ventromedial region pairs (n = 1227), no synchronization was observed. Oscillation and synchronicity intensity decline along the STN dorsolateral-ventromedial axis suggesting a fuzzy border between the STN regions. Synchronization strength was significantly correlated to the oscillation power, but synchronization was no longer observed following shuffling. We conclude that STN long-range beta oscillatory synchronization is due to increased neuronal coupling in the Parkinsonian brain and does not merely reflect the outcome of oscillations at similar frequency. The neural synchronization in the dorsolateral (probably the motor domain) STN probably augments the pathological changes in firing rate and patterns of subthalamic neurons in PD patients.

Frontal alpha-delta EEG does not preclude volitional response during anaesthesia: prospective cohort study of the isolated forearm technique

Background The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept. Methods Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power-frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling. Results Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power-frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders. Conclusions Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia. Clinical trial registration NCT02248623.

Spiking in auditory cortex following thalamic stimulation is dominated by cortical network activity.

The state of the sensory cortical network can have a profound impact on neural responses and perception. In rodent auditory cortex, sensory responses are reported to occur in the context of network events, similar to brief UP states, that produce “packets” of spikes and are associated with synchronized synaptic input (Bathellier et al., 2012; Hromadka et al., 2013; Luczak et al., 2013). However, traditional models based on data from visual and somatosensory cortex predict that ascending sensory thalamocortical (TC) pathways sequentially activate cells in layers 4 (L4), L2/3, and L5. The relationship between these two spatio-temporal activity patterns is unclear. Here, we used calcium imaging and electrophysiological recordings in murine auditory TC brain slices to investigate the laminar response pattern to stimulation of TC afferents. We show that although monosynaptically driven spiking in response to TC afferents occurs, the vast majority of spikes fired following TC stimulation occurs during brief UP states and outside the context of the L4>L2/3>L5 activation sequence. Specifically, monosynaptic subthreshold TC responses with similar latencies were observed throughout layers 2–6, presumably via synapses onto dendritic processes located in L3 and L4. However, monosynaptic spiking was rare, and occurred primarily in L4 and L5 non-pyramidal cells. By contrast, during brief, TC-induced UP states, spiking was dense and occurred primarily in pyramidal cells. These network events always involved infragranular layers, whereas involvement of supragranular layers was variable. During UP states, spike latencies were comparable between infragranular and supragranular cells. These data are consistent with a model in which activation of auditory cortex, especially supragranular layers, depends on internally generated network events that represent a non-linear amplification process, are initiated by infragranular cells and tightly regulated by feed-forward inhibitory cells.

Is consciousness fragile

It is not surprising if anaesthetists think that eliminating consciousness is easy. After all, we put patients to ‘sleep’ every day, many times a day, and we do so reliably with any of a number of agents. Anaesthetic unresponsiveness can be induced by increasing γ-aminobutyric acid type A transmission (etomidate, propofol, and benzodiazepines), decreasing N-methyl--aspartate transmission (ketamine), augmenting α2-adrenergic signalling (dexmedetomidine), or combining effects on multiple neurotransmitters and receptors (volatile anaesthetics). Unresponsiveness can even be induced by injection of tiny doses of anaesthetics into certain regions of the brain. No wonder, then, that consciousness has come to be seen as fragile. This notion is only reinforced when we consider that we can become mildly unresponsive when falling asleep spontaneously or that a mere blow to the head, a faint, or a reduction of a few degrees in core body temperature can induce a coma-like state. This common notion can be summarized as follows: it is easy to induce unresponsiveness; hence, consciousness must be fragile. The problem with this notion is that unresponsiveness is often an inadequate proxy for unconsciousness. Properly defined, consciousness is synonymous with subjective experience (seeing sights, hearing sounds, feeling pain, and having thoughts) whether or not these conscious contents relate to the environment. Thus, one is vividly conscious not only when awake and interacting with the environment, but also when dreaming, daydreaming, or during hallucinations in delirium. Therefore, it is possible that, at least in some instances, one may be surgically unresponsive yet still conscious, 5 6 a situation that is exacerbated by neuromuscular block, 8 which necessarily dissociates responsiveness from consciousness. Is consciousness fragile during anaesthesia?