John T. Gale

Mechanisms of action of deep brain stimulation (DBS)

Deep brain stimulation (DBS) is remarkably effective for a range of neurological and psychiatric disorders that have failed pharmacological and cell transplant therapies. Clinical investigations are underway for a variety of other conditions. Yet, the therapeutic mechanisms of action are unknown. In addition, DBS research demonstrates the need to re-consider many hypotheses regarding basal ganglia physiology and pathophysiology such as the notion that increased activity in the globus pallidus internal segment is causal to Parkinsons disease symptoms. Studies reveal a variety of apparently discrepant results. At the least, it is unclear which DBS effects are therapeutically effective. This systematic review attempts to organize current DBS research into a series of unifying themes or issues such as whether the therapeutic effects are local or systems-wide or whether the effects are related to inhibition or excitation. A number of alternative hypotheses are offered for consideration including suppression of abnormal activity, striping basal ganglia output of misinformation, reduction of abnormal stochastic resonance effects due to increased noise in the disease state, and reinforcement of dynamic modulation of neuronal activity by resonance effects.

Risk factors for hemorrhage during microelectrode-guided deep brain stimulation and the introduction of an improved microelectrode design.

OBJECTIVEHemorrhage is an infrequent but potentially devastating complication of deep brain stimulation (DBS) surgery. We examined the factors associated with hemorrhage after DBS surgery and evaluated a modified microelectrode design that may improve the safety of this procedure. METHODSAll microelectrode-guided DBS procedures performed at our institution between January 2000 and March 2008 were included in this study. A new microelectrode design with decreased diameter was introduced in May 2004, and data from the 2 types of electrodes were compared. RESULTSWe examined 246 microelectrode-guided lead implantations in 130 patients. Postoperative imaging revealed 7 hemorrhages (2.8%). Five of the 7 (2.0%) resulted in focal neurological deficits, all of which resolved within 1 month with the exception of 1 patient lost to follow-up. The new microelectrode design significantly decreased the number of hemorrhages (P = 0.04). A surgical trajectory traversing the ventricle also contributed significantly to the overall hemorrhage rate (P = 0.02) and specifically to the intraventricular hemorrhage rate (P = 0.01). In addition, the new microelectrode design significantly decreased the rate of intraventricular hemorrhage, given a ventricular penetration (P = 0.01). The mean age of patients with hemorrhage was significantly higher than that of patients without hemorrhage (P = 0.02). Hypertension, sex, and number of microelectrodes passed did not significantly contribute to hemorrhage rates in our population. CONCLUSIONThe rate of complications after DBS surgery is not uniformly distributed across all cases. In particular, the rates of hemorrhage were increased in older patients. Importantly, transventricular electrode trajectories appeared to increase the risk of hemorrhage. A new microelectrode design minimizing the volume of brain parenchyma penetrated during microelectrode recording leads to decreased rates of hemorrhage, particularly if the ventricles are breached.

Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex

Epileptic cortex is characterized by paroxysmal electrical discharges. Analysis of these interictal discharges typically manifests as spike-wave complexes on electroencephalography, and plays a critical role in diagnosing and treating epilepsy. Despite their fundamental importance, little is known about the neurophysiological mechanisms generating these events in human focal epilepsy. Using three different systems of microelectrodes, we recorded local field potentials and single-unit action potentials during interictal discharges in patients with medically intractable focal epilepsy undergoing diagnostic workup for localization of seizure foci. We studied 336 single units in 20 patients. Ten different cortical areas and the hippocampus, including regions both inside and outside the seizure focus, were sampled. In three of these patients, high density microelectrode arrays simultaneously recorded between 43 and 166 single units from a small (4 mm x 4 mm) patch of cortex. We examined how the firing rates of individual neurons changed during interictal discharges by determining whether the firing rate during the event was the same, above or below a median baseline firing rate estimated from interictal discharge-free periods (Kruskal-Wallis one-way analysis, P<0.05). Only 48% of the recorded units showed such a modulation in firing rate within 500 ms of the discharge. Units modulated during the discharge exhibited significantly higher baseline firing and bursting rates than unmodulated units. As expected, many units (27% of the modulated population) showed an increase in firing rate during the fast segment of the discharge (+ or - 35 ms from the peak of the discharge), while 50% showed a decrease during the slow wave. Notably, in direct contrast to predictions based on models of a pure paroxysmal depolarizing shift, 7.7% of modulated units recorded in or near the seizure focus showed a decrease in activity well ahead (0-300 ms) of the discharge onset, while 12.2% of units increased in activity in this period. No such pre-discharge changes were seen in regions well outside the seizure focus. In many recordings there was also a decrease in broadband field potential activity during this same pre-discharge period. The different patterns of interictal discharge-modulated firing were classified into more than 15 different categories. This heterogeneity in single unit activity was present within small cortical regions as well as inside and outside the seizure onset zone, suggesting that interictal epileptiform activity in patients with epilepsy is not a simple paroxysm of hypersynchronous excitatory activity, but rather represents an interplay of multiple distinct neuronal types within complex neuronal networks.

From symphony to cacophony : Pathophysiology of the human basal ganglia in Parkinson disease

Despite remarkable advances, the relationship between abnormal neuronal activity and the clinical manifestations of Parkinson disease (PD) remains unclear. Numerous hypotheses have emerged to explain the relationship between neuronal activity and symptoms such as tremor, rigidity and akinesia. Among these are the antagonist balance hypothesis wherein increased firing rates in the indirect pathway inhibits movement; the selectivity hypothesis wherein loss of neuronal selectivity leads to an inability to select or initiate movements; the firing pattern hypothesis wherein increased oscillation and synchronization contribute to tremor and disrupt information flow; and the learning hypothesis, wherein the basal ganglia are conceived as playing an important role in learning sensory-motor associations which is disrupted by the loss of dopamine. Deep brain stimulation (DBS) surgery provides a unique opportunity to assess these different ideas since neuronal activity can be directly recorded from PD patients. The emerging data suggest that the pathophysiologic changes include derangements in the overall firing rates, decreased neuronal selectivity, and increased neuronal oscillation and synchronization. Thus, elements of all hypotheses are present, emphasizing that the loss of dopamine results in a profound and multifaceted disruption of normal information flow through the basal ganglia that ultimately leads to the signs and symptoms of PD.

Subthalamic Nucleus Discharge Patterns during Movement in the Normal Monkey and Parkinsonian Patient

The pathophysiology of Parkinson disease (PD) is characterized by derangements in the discharge rates, bursting patterns, and oscillatory activity of basal ganglia (BG) neurons. In this study, subthalamic nucleus (STN) neuronal activity patterns in humans with PD were compared with that in the normal monkey during performance of similar volitional movements. Single-unit STN recordings were collected while PD patients and animals moved a joystick in the direction of targets presented on a monitor. When discharge rates in all PD human and normal monkey neurons were compared, no significant differences were observed. However, when neurons were classified by peri-movement response type (i.e., excited, inhibited, or unresponsive to movement) statistical differences were demonstrated - most significantly among PD excited neurons. Analysis of burst activity demonstrated inter- and intra-burst activities were greater in the PD human compared to the monkey irrespective of neuronal response type. Moreover, simultaneously recorded neurons in the human demonstrated consistent oscillatory synchronization at restricted frequency bands, whereas synchronized oscillatory neurons in the monkey were not restricted to distinct frequencies. During movement, discharge and burst rates were positively correlated, independent of subject or neuronal response type; however, rates and oscillatory activity were more strongly correlated in the PD human than the normal monkey. Interestingly, across all domains of analysis, STN neurons in PD demonstrated reduced response variability when compared to STN neurons in the normal monkey brain. Thus, the net effect of PD may be a reduction in the physiological degrees of freedom of BG neurons with diminished information carrying capacity.

Basal Ganglia Neurons Dynamically Facilitate Exploration During Associative Learning

The basal ganglia (BG) appear to play a prominent role in associative learning, the process of pairing external stimuli with rewarding responses. Accumulating evidence suggests that the contributions of various BG components may be described within a reinforcement learning model, in which a broad repertoire of possible responses to environmental stimuli are evaluated before the most profitable one is chosen. The striatum receives diverse cortical inputs, providing a rich source of contextual information about environmental cues. It also receives projections from midbrain dopaminergic neurons, whose phasic activity reflects a reward prediction error signal. These coincident information streams are well suited for evaluating responses and biasing future actions toward the most profitable response. Still lacking in this model is a mechanistic description of how initial response variability is generated. To investigate this question, we recorded the activity of single neurons in the globus pallidus internus (GPi), the primary BG output nucleus, in nonhuman primates (Macaca mulatta) performing a motor associative learning task. A subset (29%) of GPi neurons showed learning-related effects, decreasing firing during the early stages of learning, then returning to higher baseline rates as associations were mastered. On a trial-by-trial basis, lower firing rates predicted exploratory behavior, whereas higher rates predicted an exploitive response. These results suggest that, during associative learning, BG output is initially permissive, allowing exploration of a variety of responses. Once a profitable response is identified, increased GPi activity suppresses alternative responses, sharpening the response profile and encouraging exploitation of the profitable learned behavior.

Defense-Like Behaviors Evoked by Pharmacological Disinhibition of the Superior Colliculus in the Primate

Stimulation of the intermediate and deep layers of superior colliculus (DLSC) in rodents evokes both orienting/pursuit (approach) and avoidance/flight (defense) responses (Dean et al., 1989). These two classes of response are subserved by distinct output projections associated with lateral (approach) and medial (defense) DLSC (Comoli et al., 2012). In non-human primates, DLSC has been examined only with respect to orienting/approach behaviors, especially eye movements, and defense-like behaviors have not been reported. Here we examined the profile of behavioral responses evoked by activation of DLSC by unilateral intracerebral infusions of the GABAA receptor antagonist, bicuculline methiodide (BIC), in nine freely moving macaques. Across animals, the most consistently evoked behavior was cowering (all animals), followed by increased vocalization and escape-like behaviors (seven animals), and attack of objects (three animals). The effects of BIC were dose-dependent within the range 2.5–14 nmol (threshold dose of 4.6 nmol). The behaviors and their latencies to onset did not vary across different infusion sites within DLSC. Cowering and escape-like behaviors resembled the defense-like responses reported after DLSC stimulation in rats, but in the macaques these responses were evoked from both medial and lateral sites within DLSC. Our findings are unexpected in the context of an earlier theoretical perspective (Dean et al., 1989) that emphasized a preferential role of the primate DLSC for approach rather than defensive responses. Our data provide the first evidence for induction of defense-like behaviors by activation of DLSC in monkeys, suggesting that the role of DLSC in responding to threats is conserved across species.

Single-Neuron Responses in the Human Nucleus Accumbens during a Financial Decision-Making Task

Linking values to actions and evaluating expectations relative to outcomes are both central to reinforcement learning and are thought to underlie financial decision-making. However, neurophysiology studies of these processes in humans remain limited. Here, we recorded the activity of single human nucleus accumbens neurons while subjects performed a gambling task. We show that the nucleus accumbens encodes two signals related to subject behavior. First, we find that under relatively predictable conditions, single neuronal activity predicts future financial decisions on a trial-by-trial basis. Interestingly, we show that this activity continues to predict decisions even under conditions of uncertainty (e.g., when the probability of winning or losing is 50/50 and no particular financial choice predicts a rewarding outcome). Furthermore, we find that this activity occurs, on average, 2 s before the subjects physically manifest their decision. Second, we find that the nucleus accumbens encodes the difference between expected and realized outcomes, consistent with a prediction error signal. We show this activity occurs immediately after the subject has realized the outcome of the trial and is present on both the individual and population neuron levels. These results provide human single neuronal evidence that the nucleus accumbens is integral in making financial decisions.

Electrical Stimulation-Evoked Dopamine Release in the Primate Striatum

Background: Primate studies demonstrate that high-frequency electrical stimulation (HFS) of the caudate can enhance learning. Importantly, in these studies, stimulation was applied following the execution of behavior and the effect persisted into subsequent trials, suggesting a change in plasticity rather than a momentary facilitation of behavior. Objectives/Methods: Although the mechanism of HFS-enhanced learning is not understood, evidence suggests that dopamine plays a critical role. Therefore, we used in vivo amperometry to evaluate the effects of HFS on striatal dopamine release in the anesthetized primate. While this does not directly examine dopamine during learning, it provides insight with relation to dopamine dynamics during electrical stimulation and specifically between different stimulation parameters and striatal compartments. Results: We demonstrate that HFS results in significantly more dopamine release in the striatum compared to low-frequency stimulation. In addition, electrical stimulation operates differentially on specific neuronal elements, as the parameters for dopamine release are different for the caudate, putamen and medial forebrain bundle. Conclusions: While not direct evidence, these data suggest that HFS evokes significant dopamine release which may play a role in stimulation-enhanced learning. Moreover, these data suggest a means to modulate extracellular dopamine with a high degree of temporal and spatial precision for either research or clinical applications.

Dynamics of Propofol-Induced Loss of Consciousness Across Primate Neocortex

The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We show that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting ∼3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. SIGNIFICANCE STATEMENT How information is processed by the brain during awake and anesthetized states and, crucially, during the transition is not clearly understood. We demonstrate that neuronal dynamics are very different within an interconnecting cortical network (primary somatosensory and frontal premotor area) during the loss of consciousness (LOC) induced by propofol in nonhuman primates. Coherent beta oscillations between these regions are disrupted before LOC. Pronounced but brief gamma-band oscillations appear to correspond to LOC. In addition, neurons in both of these cortices transition from responding to both tactile and auditory stimulation before LOC to only tactile modality during unconsciousness. We demonstrate that propofol-induced LOC is accompanied by spatiotemporally distinctive neuronal dynamics in this network with concurrent changes in multisensory processing.