Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model

WM deteriorations in the model can be ameliorated by compensations that restore E/I balance.

“Finally, as proof-of-principle, we demonstrate that WM deteriorations in the model can be ameliorated by compensations that restore E/I balance.”

• Also stated in: § Introduction · boosted

  “Finally, as proof-of-principle, we demonstrate that synaptic compensations that restore E/I balance in the model can ameliorate the effects of disinhibition.”

If G_EE is reduced in greater proportion than G_EI, the bump width is decreased.

“In contrast, if G EE is reduced in greater proportion, the bump width is decreased (upper left corner in Fig. 3).”

• AssumptionThe authors state this as an assumption: All recurrent excitatory synapses are mediated by NMDARs.

Disinhibition increases the range of distractors that can interfere with WM.

“At the behavioral level, disinhibition increases deterioration over time of the precision of stored information during WM and increases the range of distractors that can interfere with WM.”

• AssumptionRests on an assumption: Robust WM requires shielding internal representations from interference by both internal noise and external distraction.

If an accuracy threshold for correct responses is introduced, the error rate is increased under disinhibition.

“If we introduce an accuracy threshold for correct responses (indicated with gray circles in Fig. 4C), the error rate is increased under disinhibition (Fig. 4D).”

• AssumptionThe authors state this as an assumption: NMDAR perturbation on inhibitory interneurons weakens recruitment of feedback inhibition.

If G_EI and G_EE are reduced together in a particular proportion, the bump width is unaltered, indicating E/I balance is maintained.

“Here, we found that if G EI and G EE are reduced together in a particular proportion to each other, the bump width is unaltered, that is, E/I balance is maintained.”

• AssumptionThe authors state this as an assumption: All recurrent excitatory synapses are mediated by NMDARs.

Disinhibition also increases firing rates of interneurons, though to a lesser degree than in pyramidal cells.

“Disinhibition also increases the firing rates of interneurons, though to a lesser degree than in pyramidal cells.”

• AssumptionThe authors state this as an assumption: NMDAR perturbation on inhibitory interneurons weakens recruitment of feedback inhibition.

Excitation in the network is dynamically balanced with inhibition, since increased pyramidal cell activity enhances activity of interneurons that deliver feedback inhibition.

“Excitation in the network is dynamically balanced with inhibition, since increased pyramidal cell activity enhances the activity of interneurons that deliver feedback inhibition.”

• AssumptionThe authors state this as an assumption: The network model represents a local microcircuit in prefrontal cortex.

The model exhibits a random drift of the angular location encoded by the WM bump.

“Similar to experimental findings, the model exhibits a random drift of the angular location encoded by the WM bump.”

• AssumptionThe authors state this as an assumption: The network model represents a local microcircuit in prefrontal cortex.

Disinhibition increases the rate at which the variance of the encoded angle grows.

“We found that disinhibition increases the rate at which the variance grows (Fig. 4B,E).”

• AssumptionThe authors state this as an assumption: NMDAR perturbation on inhibitory interneurons weakens recruitment of feedback inhibition.

If E/I imbalance is substantial, either too elevated or too reduced, network multistability is lost.

“If E/I imbalance is substantial, either too elevated or too reduced, we observe a loss of network multistability.”

At the behavioral level, disinhibition increases deterioration over time of the precision of stored information during WM.

“At the behavioral level, disinhibition increases deterioration over time of the precision of stored information during WM and increases the range of distractors that can interfere with WM.”

• AssumptionRests on an assumption: Robust WM requires shielding internal representations from interference by both internal noise and external distraction.

The variance of the encoded angle grows throughout the delay.

“As expected, the variance of the encoded angle grows throughout the delay (Fig. 4B).”

• AssumptionThe authors state this as an assumption: The network model represents a local microcircuit in prefrontal cortex.

Network multistability is preserved at 3.25% reduction of G_EI.

“Notably, network multistability is preserved at this level of disinhibition (i.e. the baseline state and WM bump states remain stable).”

• AssumptionThe authors state this as an assumption: NMDAR perturbation on inhibitory interneurons weakens recruitment of feedback inhibition.

Ketamine increased errors in a pattern predicted by the model, specifically for nontarget test probes similar to remembered targets.

“Ketamine increased errors in a pattern predicted by the model.”

• Also stated in: § Introduction · plain

  “It was found that performance errors increased with ketamine specifically for those nontarget test probes that are similar to the remembered targets, as predicted by the model.”

As the network integrates noise, the variability of report increases with delay duration.

“As the network integrates noise, the variability of report increases with delay duration (Compte et al. 2000;Chow and Coombes 2006;Carter and Wang 2007).”

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• cites Chow and Coombes 2006Not checked yet

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• AssumptionThe authors state this as an assumption: The network model represents a local microcircuit in prefrontal cortex.

Report variance and distractibility windows reduced toward their control values under both compensations.

“Report variance and distractibility windows reduced toward their control values (Fig. 7D,E).”

Disinhibition changes the shape of the distractibility curve.

“In addition to widening the distractibility window, disinhibition changes the shape of the distractibility curve shown in Figure 5B.”

Following ketamine infusion, there was a significantly greater number of false alarms for near but not far distraction (t (19) = 4.09, P < 0.0007, Cohen's d = 1.1).

“As predicted, the interaction effect was driven by a significantly greater number of false alarms following ketamine infusion for near but not far distraction (t (19) = 4.09, P < 0.0007, Cohen's d = 1.1), whereas this effect was substantially attenuated and did not reach significance for placebo trials (t (19) = 0.99, P = 0.33, Cohen's d = 0.25).”

Implemented in conjunction with the disinhibition manipulation, both compensations reduced the width of the bump attractor.

“Implemented in conjunction with our disinhibition manipulation, both compensations reduced the width of the bump attractor (Fig. 7A,B).”

When the distractor is spatially far from the target, there is no overlap between the neural representations of the distractor and of the target in working memory.

“When the distractor is spatially far from target, there is no overlap between the neural representations of the distractor and of the target in WM.”

The decrease in baseline firing was smaller for the GABAergic compensation than for the glutamatergic compensation.

“We observed that the decrease in baseline firing was smaller for the GABAergic compensation, indicating that strengthening GABAR conductance on pyramidal cells is more effective at reducing bump width than at reducing baseline firing rates in the model.”

Model behavior exhibits a dependence on target-distractor similarity.

“Interestingly, model behavior also exhibits a dependence on target-distractor similarity.”

Attraction by the distractor occurs when there is overlap between the neural representations of the target in working memory and of the distractor.

“As noted, attraction by the distractor occurs when there is overlap between the neural representations of the target in WM and of the distractor.”

When examining miss trials, there was no significant difference across infusions (t (19) = 0.72, P = 0.35).

“Moreover, when examining miss trials there was no significant difference across infusions (t (19) = 0.72, P = 0.35).”

Disinhibition increases the width of the bump such that a far distractor is transformed to a near distractor.

“As predicted, disinhibition increases the width of the bump such that a far distractor is transformed to a near distractor (Fig. 5A).”

At the behavioral level, both compensations ameliorated working memory deficits observed under disinhibition.

“At the behavioral level, both compensations ameliorated WM deficits observed under disinhibition.”

For an intermediate range within the distractibility window, disinhibition decreases the magnitude of deflection toward the distractor.

“Interestingly, for an intermediate range within the distractibility window, disinhibition decreases the magnitude of deflection toward the distractor, which may be attributed to greater”

Experimental results revealed a significant infusion by distance interaction (F 1,19 = 7.55, P < 0.015).

“Experimental results revealed a significant infusion × distance interaction (F 1,19 = 7.55, P < 0.015).”

In the model, the distractibility window is dependent on the width of the working memory bump.

“In the model, the distractibility window is dependent on the width of the WM bump.”

When the distractor is near the target, there is overlap between the distractor and target representations.

“In contrast, when the distractor is near the target, there is overlap between the distractor and target representations.”

If E/I balance is disrupted by a change at one site in the network, it can be restored through a compensatory change at another site (e.g., reduction in G EE compensating for reduction in G EI).

“As illustrated in the parameter space characterization in Figure 3, if E/I balance is disrupted by a change at one site in the network, it can be restored through a compensatory change at another site (e.g.reduction in G EE compensating for reduction in G EI ).”

Bump width increases as a function of the degree of disinhibition.

“Increase of bump width as a function of the degree of disinhibition.”

Disinhibition degrades memory precision.

“Disinhibition degrades memory precision due to increased noise-induced drift.”

The distractibility window varies with bump width as E/I balance is perturbed.

“We find that the distractibility window varies with bump width as E/I balance is perturbed.”

In contrast, our study focused on more subtle effects that occur within the multistability regime.

“In contrast, our study focused on more subtle effects that occur within the multistability regime (Fig. 3).”

Bump width can be maintained with a proportional decrease in both G_EI and G_EE.

“Bump width can be maintained with a proportional decrease in both G EI and G EE .”

Baseline firing rates increase as a function of the degree of disinhibition for both pyramidal cells and interneurons, from control values of 1 and 6.4 Hz, respectively.

“Increase of baseline firing rates as a function of the degree of disinhibition for both pyramidal cells and interneurons, from their control values of 1 and 6.4 Hz, respectively.”

The baseline state is destabilized due to strong disinhibition in the white region.

“In the white region at the bottom right corner, the baseline state is destabilized, due to strong disinhibition.”

Disinhibition increases noise-induced drift.

“Disinhibition degrades memory precision due to increased noise-induced drift.”

The network supports both a low-rate symmetric baseline state and a family of working memory bump states in the multistability region.

“The colored diagonal band is the region with multistability, in which the network supports both a low-rate symmetric baseline state and a family of WM bump states.”

The width of the working memory bump is controlled by E/I balance.

“The width of the WM bump is controlled by E/I balance.”

NMDAR hypofunction on interneurons weakens the recruitment of feedback inhibition.

“NMDAR hypofunction on interneurons (1; decreased NMDAR conductance on interneurons, G EI ) weakens the recruitment of feedback inhibition.”

Disinhibition broadens the network activity pattern / working memory representation.

“Disinhibition broadens the network activity pattern.”

• Also stated in: § Future Directions · plain

  “Disinhibition broadens WM representation.”

Increasing E/I ratio, and thereby bump width, degrades working memory robustness in a manner that yields specific types of errors.

“Increasing E/I ratio, and thereby bump width, degrades WM robustness in a manner that yields specific types of errors.”

The bump state is destabilized due to insufficient recurrent excitation in the black region.

“In the black region at the top left corner, the bump state is destabilized, due to insufficient recurrent excitation.”

The compensations restore the bump width from its broadened value under disinhibition to near its control value.

“The compensations restore the bump width from its broadened value under disinhibition to near its control value.”

Ketamine induces errors in spatial working memory specifically for near distractors.

“Ketamine induces errors in spatial WM specifically for near distractors, as predicted by the model.”

• Also stated in: § Future Directions · plain

  “Ketamine degrades performance selectively, increasing false alarms to near distractor probes (**P < 0.01), but not false alarms to far distractor probes or misses to target probes (not significant).”

Disinhibition is detrimental to the network's ability to filter out nonlocal distractors.

“Disinhibition is detrimental the network's ability to filter out nonlocal distractors.”

Overlap between probe representations and the target representation in working memory is larger for disinhibition than for control.

“Overlap between the probe representations (gray) and the target representation in WM is larger for disinhibition (orange) than for control (blue).”

The variance of the encoded angle fluctuations grows with time during the delay.

“The variance of the encoded angle fluctuations grows with time during the delay.”

Report variance after a 3-s delay increases as a function of the degree of disinhibition.

“Increase of the report variance, after a 3-s delay, as a function of the degree of disinhibition.”

The disinhibition of the spontaneous firing rate is ameliorated by the compensations, particularly the glutamatergic manipulation.

“The disinhibition of the spontaneous firing rate is ameliorated by the compensations, particularly the glutamatergic manipulation.”

The distractibility window increases as a function of the degree of disinhibition.

“Increase of the distractibility window as a function of the degree of disinhibition.”

Model performance under disinhibition replicates the observation of the human study that the error rate is differentially increased for false alarms to near distractor probes.

“Model performance under disinhibition replicates the observation of the human study that the error rate is differentially increased for false alarms to near distractor probes.”

The report variance after a 3-s delay is reduced to near the control level by the compensations.

“The report variance, after a 3-s delay, is reduced to near the control level by the compensations.”

The distractibility window is widened by disinhibition.

“The distractibility window is widened by disinhibition.”

Overlap increases most for the near distractor location.

“Overlap increases most for the near distractor location.”

The distractibility window is reduced to near the control level by the compensations.

“The distractibility window is reduced to near the control level by the compensations.”

During the delay period, the encoded angle undergoes random drift due to internal noise introduced by Poisson background input.

“During the delay period, the encoded angle undergoes random drift, due to internal noise introduced by the Poisson background input.”

• AssumptionThe authors state this as an assumption: The network model represents a local microcircuit in prefrontal cortex.

The filtering function of WM may be severely compromised in schizophrenia.

“This”

• cites Anticevic et al. 2011 sourceNot checked yet

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The net effect of mild reductions in excitatory drive on neural WM activity can be described by the net change to E/I balance.

“Taken together, these results show that the net effect of mild reductions in excitatory drive on neural WM activity can be described by the net change to E/I balance.”

WM representations depend critically on E/I balance.

“Primate electrophysiological studies show that persistent firing of prefrontal pyramidal cells supports robust and stable WM representations (Funahashi et al. 1989) that depend critically on E/I balance (Rao et al. 2000).”

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E/I ratio is the critical parameter for network function, rather than the absolute strength of either G_EI or G_EE alone.

“This suggests that E/I ratio is the critical parameter for network function, rather than the absolute strength of either G EI or G EE alone.”

• AssumptionThe authors state this as an assumption: All recurrent excitatory synapses are mediated by NMDARs.

E/I balance is a fundamental property of cortical microcircuitry.

“Excitation-inhibition balance (E/I balance) is a fundamental property of cortical microcircuitry.”

• Also stated in: § Introduction · plain

  “A basic principle of cortical computation is the dynamically balanced interaction of excitatory pyramidal cells and inhibitory interneurons (Shadlen and Newsome 1994;van Vreeswijk and Sompolinsky 1996;Shu et al. 2003).”

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Biophysically realistic computational models have delineated a neural circuit basis of WM activity through strong recurrent excitation to sustain persistent activity and recruitment of lateral inhibition to shape selectivity.

“Biophysically realistic computational models have delineated a neural circuit basis of WM activity through 2 key network properties: Strong recurrent excitation to sustain persistent activity and recruitment of lateral inhibition to shape selectivity of representations (Compte et al. 2000;Brunel and Wang 2001).”

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• cites Brunel and Wang 2001 sourceNot checked yet

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Schizophrenia involves a severe deficit in working memory.

“with a severe deficit in working memory (WM), the ability to transiently maintain and manipulate information internally (Goldman-Rakic 1994;Lee and Park 2005).”

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Prefrontal cortex exhibits altered inhibitory microcircuitry in schizophrenia.

“The prefrontal cortex is a key node in the distributed cortical network recruited during WM (Owen et al. 2005;Fuster 2008) and exhibits altered inhibitory microcircuitry in schizophrenia (Lewis et al. 2005;Bitanihirwe et al. 2009).”

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Persistent firing of prefrontal pyramidal cells supports robust and stable WM representations.

“Primate electrophysiological studies show that persistent firing of prefrontal pyramidal cells supports robust and stable WM representations (Funahashi et al. 1989) that depend critically on E/I balance (Rao et al. 2000).”

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A broadened bump under disinhibition is subjected to more background noise input.

“A broadened bump under disinhibition is therefore subjected to more background noise input.”

• AssumptionThe authors state this as an assumption: NMDAR perturbation on inhibitory interneurons weakens recruitment of feedback inhibition.

Prefrontal cortex is a key node in the distributed cortical network recruited during WM.

“The prefrontal cortex is a key node in the distributed cortical network recruited during WM (Owen et al. 2005;Fuster 2008) and exhibits altered inhibitory microcircuitry in schizophrenia (Lewis et al. 2005;Bitanihirwe et al. 2009).”

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The greater loss of WM precision over time captures prior experimental observations of behavior in schizophrenia.

“This greater loss of WM precision over time captures prior experimental observations of behavior in schizophrenia (Badcock et al. 2008).”

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The selective increase in the number of errors for false alarms to near nontarget probes, but neither for false alarms to far nontarget probes nor for misses, is in line with the model prediction.

“This selective increase in the number of errors for false alarms to near nontarget probes, but neither for false alarms to far nontarget probes nor for misses, is in line with the model prediction.”

The core model prediction is that working memory representations are broadened under disinhibition, due to disrupted E/I balance.

“As described above, the core model prediction is that WM representations are broadened under disinhibition, due to disrupted E/I balance.”

At low concentrations employed in human experimental work, ketamine's effects may involve a preferential blockade of NMDAR subunits that are expressed more in interneurons than in pyramidal cells.

“While the precise pathways by which ketamine induces disinhibition are not fully resolved, at the low concentrations employed in human experimental work, there is evidence that its effects may involve a preferential blockade of NMDAR subunits (Kotermanski and Johnson 2009) that are expressed more in interneurons than in pyramidal cells (Xi et al. 2009).”

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Manipulating target-distractor similarity to measure the distractibility window may be a highly sensitive experimental probe of changes in the neural working memory representation.

“This model finding also suggests that manipulating target-distractor similarity (to measure the distractibility window) may be a highly sensitive experimental probe of changes in the neural WM representation (see Discussion).”

A recent psychophysical study using a similar spatial working memory match/nonmatch task found that, relative to healthy controls, individuals with schizophrenia also exhibit a selective increase in false alarms for near nontarget probes but not for far nontarget probes.

“Interestingly, a recent psychophysical study using a similar spatial WM match/nonmatch task found that, relative to healthy controls, individuals with schizophrenia also exhibit a selective increase in false alarms for near nontarget probes but not for far nontarget probes (Mayer and Park 2012).”

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In visuospatial working memory, similarity is determined by the spatial separation between the target and the distractor.

“In visuospatial WM, similarity is determined by the spatial separation between the target and the distractor.”

In memory-guided saccade tasks, variability of saccade endpoints increases with delay duration.

“In memory-guided saccade tasks, variability of saccade endpoints increases with delay duration (Funahashi et al., 1989;White et al. 1994;Ploner et al. 1998).”

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In experimental settings, the effect of a distractor on working memory is largely dependent on the similarity between the distractor and the target held in memory.

“In experimental settings, the effect of a distractor on WM appears to be largely dependent on the similarity between a distractor and the target held in memory.”

• cites Van der Stigchel et al. 2007;Herwig et al. 2010Not matched

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The model predicts that the increase in errors is selective, with an increased rate of false alarms when the probe is presented at near, but not far, nontarget locations.

“The model predicts that the increase in errors is selective, with an increased rate of false alarms when the probe is presented at near, but not far, nontarget locations.”

• AssumptionThe authors state this as an assumption: The probability of a match response is a sigmoidal function of the overlap between the target and probe representations.

As a pharmacological model of schizophrenia, ketamine allows for controlled and transient NMDAR manipulation in healthy volunteers.

“As a pharmacological model of schizophrenia, ketamine allows for controlled and transient NMDAR manipulation in healthy volunteers (Krystal et al. 2003).”

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Ketamine-induced neural disinhibition effects can be observed in both in vitro and in vivo.

“Ketamine-induced neural disinhibition effects can be observed in both in vitro and in vivo (Greene 2001).”

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In neural circuit models of match/nonmatch decision making, the probability of a match response is a monotonically increasing function of the overlap between the neural representations of the probe and of the target in working memory.

“In neural circuit models of match/nonmatch decision making, the probability of match response is a monotonically increasing function of the overlap between the neural representations of the probe and of the target in WM (Tagamets and Horwitz 1998;Engel and Wang 2011).”

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Strengthening GABAR conductance on pyramidal cells is more effective at reducing bump width than at reducing baseline firing rates in the model.

“We observed that the decrease in baseline firing was smaller for the GABAergic compensation, indicating that strengthening GABAR conductance on pyramidal cells is more effective at reducing bump width than at reducing baseline firing rates in the model.”

Changes to the working memory representation by disinhibition can potentially alter the target-probe overlap and thereby affect the pattern of responses.

“Therefore, changes to the WM representation by disinhibition can potentially alter the target-probe overlap and thereby affect the pattern of responses.”

• AssumptionThe authors state this as an assumption: The match/nonmatch decision is based on the overlap between the neural representations of the target in working memory and of the probe.

The network model is extensively validated.

“We used an extensively validated spiking network model of spatial WM, consisting of pyramidal cells and interneurons, structured in a ring architecture (Fig. 1A; Compte et al. 2000;Carter and Wang 2007).”

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The model predicts that misses should not increase since the overlap does not substantially decrease when the probe is presented at the target location.

“Similarly, the model predicts that misses should not increase since the overlap does not substantially decrease when the probe is presented at the target location.”

• AssumptionThe authors state this as an assumption: The probability of a match response is a sigmoidal function of the overlap between the target and probe representations.

The present computational model possesses an inherent resistance to distractors.

“Previous work has shown that the present computational model possesses an inherent resistance to distractors (Compte et al. 2000;Gruber et al. 2006).”

• cites Compte et al. 2000;Gruber et al. 2006Not matched

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The AMPAR/NMDAR ratio differs between pyramidal cells and fast-spiking interneurons.

“This is important in light of recent studies showing that the AMPAR/NMDAR ratio differs between pyramidal cells and fast-spiking interneurons (Wang and Gao 2009;Rotaru et al. 2011).”

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A neural circuit that subserves working memory should be resistant to intervening external distractors during the delay.

“a neural circuit that subserves WM should be resistant to intervening external distractors during the delay (Jonides et al. 2008).”

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The model suggests that E/I balance is the crucial parameter that determines working memory performance.

“The model suggests that E/I balance is the crucial parameter that determines WM performance.”

The veridical report of memoranda can help distinguish deficits in maintenance from potential deficits in the downstream target-probe comparison and match/nonmatch decision computations.

“The veridical report of memoranda can also help to distinguish deficits in maintenance from potential deficits in the downstream target-probe comparison, and match/nonmatch decision computations inherent in the match/nonmatch paradigm (Lencz et al. 2003;Zhang and Luck 2008).”

• cites Lencz et al. 2003;Zhang and Luck 2008Not matched

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Because the GABAergic compensation in the model acted only on pyramidal cells, a relatively lower level of manipulation is required to restore E/I balance.

“In contrast, because the GABAergic compensation in the model acted only on pyramidal cells, a relatively lower level of manipulation is required to restore E/I balance.”

E/I balance is important for multistability and bump width.

“The parameter space of NMDAR hypofunction highlights the importance of E/I balance for multistability and bump width.”

Distractors can serve as a sensitive probe of the underlying neural working memory representation, enabling one to measure behaviorally how neural dysfunction perturbs working memory representation.

“That is, distractors can serve as a sensitive probe of the underlying neural WM representation, enabling one to measure behaviorally how neural dysfunction perturbs WM representation.”

This work focuses on the consequences of a reduced overall strength of connections from excitatory cells to interneurons, which could be related, at least in part, to interneuron dysfunction hypothesized to operate in schizophrenia.

“This work focuses on the consequences of a reduced overall strength of connections from excitatory cells to interneurons, which could be related, at least in part, to interneuron dysfunction hypothesized to operate in schizophrenia (Lewis et al. 2005;Lisman et al. 2008;Marin 2012).”

• cites Lewis et al. 2005;Lisman et al. 2008;Marin 2012Not matched

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Because these two changes partially counteract one another, the level of the manipulation must be relatively large to restore E/I balance.

“Because these 2 changes partially counteract one another, the level of the manipulation must be relatively large to restore E/I balance.”

This increase in scatter may be subtle and difficult to detect with a categorical (e.g., match/nonmatch) design.

“This increase in scatter may be subtle and difficult to detect with a categorical (e.g.match/nonmatch) design.”

In the context of a match/nonmatch task, spontaneous bump creation at random locations would increase false alarms to far nontarget probes.

“In the context of a match/nonmatch task, spontaneous bump creation at random locations would increase false alarms to far nontarget probes.”

The neural changes are linked to behavioral deficits, namely increased susceptibility to both internal noise and external distraction.

“They are linked to behavioral deficits, namely increased susceptibility to both internal noise and external distraction.”

In a single-item spatial working memory experiment, behavioral results for schizophrenia patients were consistent with degraded precision, manifested as increased scatter of reports around the target location.

“Indeed, in a single-item spatial WM experiment, behavioral results for schizophrenia patients were consistent with degraded precision, manifested as increased scatter of reports around the target location (Badcock et al. 2008).”

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Target-distractor similarity is a critical parameter in determining the effect of distractors on working memory.

“Our findings also underscore that target-distractor similarity is a critical parameter in determining the effect of distractors on WM (Van der Stigchel et al. 2007;Herwig et al. 2010).”

• cites Van der Stigchel et al. 2007;Herwig et al. 2010Not matched

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The detailed characterization of behavior reports and error types can be harnessed to constrain which network regimes in models may correspond to experimentally studied disease states.

“The detailed characterization of behavior reports and error types can be harnessed to constrain which network regimes in models may correspond to experimentally studied disease states.”

Detecting all of these effects is dependent on the continuous nature of the present model.

“Detecting all of these effects is dependent on the continuous nature of the present model.”

The proof-of-principle compensations highlight that E/I balance is a critical property of the model that relates to observed deficits induced by disinhibition.

“Our proof-of-principle compensations further highlight that E/I balance is a critical property of the model that relates to observed deficits induced by disinhibition.”

The present model suggests that a continuous, veridical measure of the report is sensitive to detecting degraded precision due to drift.

“First, the present model suggests that a continuous, veridical measure of the report is sensitive to detecting degraded precision due to drift.”

Both of these previous computational studies focused on very strong microcircuit perturbations, to such an extent that they compromise network multistability.

“Both of these previous computational studies focused on very strong microcircuit perturbations, to such an extent that they compromise network multistability.”

• cites Loh et al. 2007;Cano-Colino and Compte 2012Not matched

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There is evidence that working memory capacity is impaired in schizophrenia.

“There is evidence that WM capacity is impaired in schizophrenia (Gold et al. 2010).”

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Compensations with greater specificity, with strong changes in either pyramidal cells or interneurons but not both, may be more efficacious than those that act equally on pyramidal cells and interneurons.

“Together, this suggests that compensations with greater specificity, with strong changes in either pyramidal cells or interneurons but not both, may be more efficacious than those that act equally on pyramidal cells and interneurons.”

The present work provides a different, complementary perspective that emphasizes the importance of the width of the population firing pattern, rather than the peak firing rate.

“The present work provides a different, complementary perspective that emphasizes the importance of the width of the population firing pattern, rather than the peak firing rate.”

Even relatively modest changes of parameters, such as the degree of disinhibition, can give rise to qualitatively different behavioral effects with vastly different clinical implications (namely loss of internal precision vs. false memory formation).

“In that sense, even relatively modest changes of parameters, such as the degree of disinhibition, can give rise to qualitatively different behavioral effects with vastly different clinical implications (namely loss of internal precision vs. false memory formation).”