A prefrontal network model operating near steady and oscillatory states links spike desynchronization and synaptic deficits in schizophrenia.

Schizophrenia results in part from a failure of prefrontal networks but we lack full understanding of how disruptions at a synaptic level cause failures at the network level. This is a crucial gap in our understanding because it prevents us from discovering how genetic mutations and environmental risks that alter synaptic function cause prefrontal network to fail in schizophrenia. To address that question, we developed a recurrent spiking network model of prefrontal local circuits that can explain the link between NMDAR synaptic and 0-lag spike synchrony deficits we recently observed in a pharmacological monkey model of prefrontal network failure in schizophrenia. We analyze how the balance between AMPA and NMDA components of recurrent excitation and GABA inhibition in the network influence oscillatory spike synchrony to inform the biological data. We show that reducing recurrent NMDAR synaptic currents prevents the network from shifting from a steady to oscillatory state in response to extrinsic inputs such as might occur during behavior. These findings strongly parallel dynamic modulation of 0-lag spike synchrony we observed between neurons in monkey prefrontal cortex during behavior, as well as the suppression of this 0-lag spiking by administration of NMDAR antagonists. As such, our cortical network model provides a plausible mechanism explaining the link between NMDAR synaptic and 0-lag spike synchrony deficits observed in a pharmacological monkey model of prefrontal network failure in schizophrenia.

Schizophrenia is a long-term mental health condition that can cause a person to see, hear or believe things that are not real. Although researchers do not fully understand the causes of schizophrenia, it is known to disrupt synapses, which connect neurons in the brain to form circuits that carry out a specific function when activated. This disruption alters the pattern of activity among the neurons, distorting the way that information is processed and leading to symptoms. Development of schizophrenia is thought to be due to interactions between many factors, including genetic makeup, changes in how the brain matures during development, and environmental stress. Despite animal studies revealing how neural circuits can fail at the level of individual cells, it remains difficult to predict or understand the complex ways that this damage affects advanced brain functions. Previous research in monkeys showed that mimicking schizophrenia using a drug that blocks a particular type of synapse prevented neurons from coordinating their activity. However, this did not address how synaptic and cellular changes lead to disrupted neural circuits. To better understand this, Crowe et al. developed a computational model of neural circuits to study how they respond to synapse disruption. To replicate the brain, the model consisted of two types of neurons ­ those that activate connecting cells in response to received signals and those that suppress them. This model could replicate the complex network behavior that causes brain cells to respond to sensory inputs. Increasing the strength of inputs to the network caused it to switch from a state in which the cells fired independently to one where the cells fired at the same time. As was previously seen in monkeys, blocking a particular type of synapse thought to be involved in schizophrenia prevented the cells from coordinating their signaling. The findings suggest that schizophrenia-causing factors can reduce the ability of neurons to fire at the same instant. Disrupting this process could lead to weaker and fewer synapses forming during brain development or loss of synapses in adults. If that is the case, and scientists can understand how factors combine to trigger this process, the mechanism of coordinated activity failure revealed by the model could help identify treatments that prevent or reverse the synapse disruption seen in schizophrenia.

Shared Neural Activity But Distinct Neural Dynamics for Cognitive Control in Monkey Prefrontal and Parietal Cortex.

To better understand how prefrontal networks mediate forms of cognitive control disrupted in schizophrenia, we translated a variant of the AX continuous performance task that measures specific deficits in the human disease to 2 male monkeys and recorded neurons in PFC and parietal cortex during task performance. In the task, contextual information instructed by cue stimuli determines the response required to a subsequent probe stimulus. We found parietal neurons encoding the behavioral context instructed by cues that exhibited nearly identical activity to their prefrontal counterparts (Blackman et al., 2016). This neural population switched their preference for stimuli over the course of the trial depending on whether the stimuli signaled the need to engage cognitive control to override a prepotent response. Cues evoked visual responses that appeared in parietal neurons first, whereas population activity encoding contextual information instructed by cues was stronger and more persistent in PFC. Increasing cognitive control demand biased the representation of contextual information toward the PFC and augmented the temporal correlation of task-defined information encoded by neurons in the two areas. Oscillatory dynamics in local field potentials differed between cortical areas and carried as much information about task conditions as spike rates. We found that, at the single-neuron level, patterns of activity evoked by the task were nearly identical between the two cortical areas. Nonetheless, distinct population dynamics in PFC and parietal cortex were evident. suggesting differential contributions to cognitive control.SIGNIFICANCE STATEMENT We recorded neural activity in PFC and parietal cortex of monkeys performing a task that measures cognitive control deficits in schizophrenia. This allowed us to characterize computations performed by neurons in the two areas to support forms of cognitive control disrupted in the disease. Subpopulations of neurons in the two areas exhibited parallel modulations in firing rate; and as a result, all patterns of task-evoked activity were distributed between PFC and parietal cortex. This included the presence in both cortical areas of neurons reflecting proactive and reactive cognitive control dissociated from stimuli or responses in the task. However, differences in the timing, strength, synchrony, and correlation of information encoded by neural activity were evident, indicating differential contributions to cognitive control.

Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits.

Schizophrenia results from hundreds of known causes, including genetic, environmental, and developmental insults that cooperatively increase risk of developing the disease. In spite of the diversity of causal factors, schizophrenia presents with a core set of symptoms and brain abnormalities (both structural and functional) that particularly impact the prefrontal cortex. This suggests that many different causal factors leading to schizophrenia may cause prefrontal neurons and circuits to fail in fundamentally similar ways. The nature of convergent malfunctions in prefrontal circuits at the cell and synaptic levels leading to schizophrenia are not known. Here, we apply convergence-guided search to identify core pathological changes in the functional properties of prefrontal circuits that lie downstream of mechanistically distinct insults relevant to the disease. We compare the impacts of blocking NMDA receptors in monkeys and deleting a schizophrenia risk gene in mice on activity timing and effective communication in prefrontal local circuits. Although these manipulations operate through distinct molecular pathways and biological mechanisms, we found they produced convergent pathophysiological effects on prefrontal local circuits. Both manipulations reduced the frequency of synchronous (0-lag) spiking between prefrontal neurons and weakened functional interactions between prefrontal neurons at monosynaptic lags as measured by information transfer between the neurons. The two observations may be related, as reduction in synchronous spiking between prefrontal neurons would be expected to weaken synaptic connections between them via spike-timing-dependent synaptic plasticity. These data suggest that the link between spike timing and synaptic connectivity could comprise the functional vulnerability that multiple risk factors exploit to produce disease.

Longitudinal analysis of local field potentials recorded from directional deep brain stimulation lead implants in the subthalamic nucleus.

Objective.The electrode-tissue interface surrounding a deep brain stimulation (DBS) lead is known to be highly dynamic following implantation, which may have implications on the interpretation of intraoperatively recorded local field potentials (LFPs). We characterized beta-band LFP dynamics following implantation of a directional DBS lead in the sensorimotor subthalamic nucleus (STN), which is a primary target for treating Parkinson's disease.Approach.Directional STN-DBS leads were implanted in four healthy, non-human primates. LFPs were recorded over two weeks and again 1-4 months after implantation. Impedance was measured for two weeks post-implant without stimulation to compare the reactive tissue response to changes in LFP oscillations. Beta-band (12-30 Hz) peak power was calculated from the LFP power spectra using both common average referencing (CAR) and intra-row bipolar referencing (IRBR).Results.Resting-state LFPs in two of four subjects revealed a steady increase of beta power over the initial two weeks post-implant whereas the other two subjects showed variable changes over time. Beta power variance across days was significantly larger in the first two weeks compared to 1-4 months post-implant in all three long-term subjects. Further, spatial maps of beta power several hours after implantation did not correlate with those measured two weeks or 1-4 months post-implant. CAR and IRBR beta power correlated across short- and long-term time points. However, depending on the time period, subjects showed a significant bias towards larger beta power using one referencing scheme over the other. Lastly, electrode-tissue impedance increased over the two weeks post-implant but showed no significant correlation to beta power.Significance.These results suggest that beta power in the STN may undergo significant changes following DBS lead implantation. DBS lead diameter and electrode recording configurations can affect the post-implant interpretation of oscillatory features. Such insights will be important for extrapolating results from intraoperative and externalized LFP recordings.

Cognitive Control Errors in Nonhuman Primates Resembling Those in Schizophrenia Reflect Opposing Effects of NMDA Receptor Blockade on Causal Interactions Between Cells and Circuits in Prefrontal and Parietal Cortices.

BACKGROUND: The causal biology underlying schizophrenia is not well understood, but it is likely to involve a malfunction in how neurons adjust synaptic connections in response to patterns of activity in networks. We examined statistical dependencies between neural signals at the cell, local circuit, and distributed network levels in prefrontal and parietal cortices of monkeys performing a variant of the AX continuous performance task paradigm. We then quantified changes in the pattern of neural interactions across levels of scale following NMDA receptor (NMDAR) blockade and related these changes to a pattern of cognitive control errors closely matching the performance of patients with schizophrenia. METHODS: We recorded the spiking activity of 1762 neurons along with local field potentials at multiple electrode sites in prefrontal and parietal cortices concurrently, and we generated binary time series indicating the presence or absence of spikes in single neurons or local field potential power above or below a threshold. We then applied causal discovery analysis to the time series to detect statistical dependencies between the signals (causal interactions) and compared the pattern of these interactions before and after NMDAR blockade. RESULTS: Global blockade of NMDAR produced distinctive and frequently opposite changes in neural interactions at the cell, local circuit, and network levels in prefrontal and parietal cortices. Cognitive control errors were associated with decreased interactions at the cell level and with opposite changes at the network level in prefrontal and parietal cortices. CONCLUSIONS: NMDAR synaptic deficits change causal interactions between neural signals at different levels of scale that correlate with schizophrenia-like deficits in cognitive control.

Differential Roles of Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in Decision-Making and State Representation in a Cognitive Control Task Measuring Deficits in Schizophrenia.

The mediodorsal nucleus of the thalamus (MD) is reciprocally connected with the prefrontal cortex (PFC), and although the MD has been implicated in a range of PFC-dependent cognitive functions (Watanabe and Funahashi, 2012; Mitchell and Chakraborty, 2013; Parnaudeau et al., 2018), little is known about how MD neurons in the primate participate specifically in cognitive control, a capability that reflects the ability to use contextual information (such as a rule) to modify responses to environmental stimuli. To learn how the MD-PFC thalamocortical network is engaged to mediate forms of cognitive control that are selectively disrupted in schizophrenia, we trained male monkeys to perform a variant of the AX continuous performance task, which reliably measures cognitive control deficits in patients (Henderson et al., 2012) and used linear multielectrode arrays to record neural activity in the MD and PFC simultaneously. We found that the two structures made clearly different contributions to distributed processing for cognitive control: MD neurons were specialized for decision-making and response selection, whereas prefrontal neurons were specialized to preferentially encode the environmental state on which the decision was based. In addition, we observed that functional coupling between MD and PFC was strongest when the decision as to which of the two responses in the task to execute was being made. These findings delineate unique contributions of MD and PFC to distributed processing for cognitive control and characterized neural dynamics in this network associated with normative cognitive control performance.SIGNIFICANCE STATEMENT Cognitive control is fundamental to healthy human executive functioning (Miller and Cohen, 2001) and deficits in patients with schizophrenia relate to decreased functional activation of the MD thalamus and the prefrontal cortex (Minzenberg et al., 2009), which are reciprocally linked (Goldman-Rakic and Porrino, 1985; Xiao et al., 2009). We carry out simultaneous neural recordings in the MD and PFC while monkeys perform a cognitive control task translated from patients with schizophrenia to relate thalamocortical dynamics to cognitive control performance. Our data suggest that state representation and decision-making computations for cognitive control are preferentially performed by PFC and MD, respectively. This suggests experiments to parse decision-making and state representation deficits in patients while providing novel computational targets for future therapies.

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia.

We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dysregulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism.

Monkey Prefrontal Neurons Reflect Logical Operations for Cognitive Control in a Variant of the AX Continuous Performance Task (AX-CPT).

Cognitive control is the ability to modify the behavioral response to a stimulus based on internal representations of goals or rules. We sought to characterize neural mechanisms in prefrontal cortex associated with cognitive control in a context that would maximize the potential for future translational relevance to human neuropsychiatric disease. To that end, we trained monkeys to perform a dot-pattern variant of the AX continuous performance task that is used to measure cognitive control impairment in patients with schizophrenia (MacDonald, 2008;Jones et al., 2010). Here we describe how information processing for cognitive control in this task is related to neural activity patterns in prefrontal cortex of monkeys, to advance our understanding of how behavioral flexibility is implemented by prefrontal neurons in general, and to model neural signals in the healthy brain that may be disrupted to produce cognitive control deficits in schizophrenia. We found that the neural representation of stimuli in prefrontal cortex is strongly biased toward stimuli that inhibit prepotent or automatic responses. We also found that population signals encoding different stimuli were modulated to overlap in time specifically in the case that information from multiple stimuli had to be integrated to select a conditional response. Finally, population signals relating to the motor response were biased toward less frequent and therefore less automatic actions. These data relate neuronal activity patterns in prefrontal cortex to logical information processing operations required for cognitive control, and they characterize neural events that may be disrupted in schizophrenia. SIGNIFICANCE STATEMENT: Functional imaging studies have demonstrated that cognitive control deficits in schizophrenia are associated with reduced activation of the dorsolateral prefrontal cortex (MacDonald et al., 2005). However, these data do not reveal how the disease has disrupted the function of prefrontal neurons to produce the observed deficits in cognitive control. Relating cognitive control to neurophysiological signals at a cellular level in prefrontal cortex is a necessary first step toward understanding how disruption of these signals could lead to cognitive control failure in neuropsychiatric disease. To that end, we translated a task that measures cognitive control deficits in patients with schizophrenia to monkeys and describe here how neural signals in prefrontal cortex relate to performance.

The importance of the basolateral/basomedial amygdala for goal-directed maternal responses in postpartum rats.

A model of the neural regulation of maternal behavior in rats proposes that the basolateral amygdala (BLA) provides pup-related sensory inputs to the nucleus accumbens-ventral pallidum (NA-VP) circuit and that medial preoptic area activation of the mesolimbic dopamine system potentiates the ability of BLA neurons to stimulate goal-directed maternal responses, such as pup retrieval behavior. Previous research using electrical lesions has provided some direct support for the importance of BLA. In the current study, we examined the effects of temporary inactivation of neurons within BLA and the adjoining basomedial nucleus of the amygdala (BMA) on maternal behavior in postpartum rats. For an anatomical control, muscimol was injected into the medial amygdala (MeA). Since research has shown that MeA plays an inhibitory role in maternal behavior, it was predicted that muscimol injections restricted to that site would not disrupt maternal behavior. The results showed that muscimol injections into BLA/BMA, at dosage levels between 100 and 200 ng/side, produced major deficits in retrieval behavior and minor deficits in nursing behavior. In contrast, muscimol injections into MeA left maternal behavior relatively unaffected. These results show that neuron-specific inactivation of BLA/BMA causes severe deficits in what can be considered a goal-directed and appetitive maternal response, pup retrieval, while leaving the consummatory aspect of maternal behavior, nursing, relatively unaffected. Since oxytocin is important for maternal behavior, and since both BMA and MeA neurons contain OT-binding sites, perhaps OT stimulates BMA output and suppresses MeA output to influence aspects of maternal behavior.