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Targeting Neural Synchrony Deficits is Sufficient to Improve Cognition in a Schizophrenia-Related Neurodevelopmental Model.

Lee H, Dvorak D, Fenton AA - Front Psychiatry (2014)

Bottom Line: We have proposed a "discoordination" hypothesis that cognitive impairment results from aberrant coordination of neural activity.We report that: (1) inter-hippocampal synchrony in the theta and beta bands is correlated with active place avoidance performance; (2) the anticonvulsant ethosuximide attenuated the abnormal spike-wave activity, improved cognitive control, and reduced hyperlocomotion; (3) ethosuximide not only normalized the task-associated theta and beta synchrony between the two hippocampi but also increased synchrony between the medial prefrontal cortex and hippocampus above control levels; (4) the antipsychotic olanzapine was less effective at improving cognitive control and normalizing place avoidance-related inter-hippocampal neural synchrony, although it reduced hyperactivity; and (5) olanzapine caused an abnormal pattern of frequency-independent increases in neural synchrony, in both NVHL and control rats.These data suggest that normalizing aberrant neural synchrony can be beneficial and that drugs targeting the pathophysiology of abnormally coordinated neural activities may be a promising theoretical framework and strategy for developing treatments that improve cognition in neurodevelopmental disorders such as schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Neural and Behavioral Science, Downstate Medical Center, State University of NewYork , Brooklyn, NY , USA.

ABSTRACT
Cognitive symptoms are core features of mental disorders but procognitive treatments are limited. We have proposed a "discoordination" hypothesis that cognitive impairment results from aberrant coordination of neural activity. We reported that neonatal ventral hippocampus lesion (NVHL) rats, an established neurodevelopmental model of schizophrenia, have abnormal neural synchrony and cognitive deficits in the active place avoidance task. During stillness, we observed that cortical local field potentials sometimes resembled epileptiform spike-wave discharges with higher prevalence in NVHL rats, indicating abnormal neural synchrony due perhaps to imbalanced excitation-inhibition coupling. Here, within the context of the hypothesis, we investigated whether attenuating abnormal neural synchrony will improve cognition in NVHL rats. We report that: (1) inter-hippocampal synchrony in the theta and beta bands is correlated with active place avoidance performance; (2) the anticonvulsant ethosuximide attenuated the abnormal spike-wave activity, improved cognitive control, and reduced hyperlocomotion; (3) ethosuximide not only normalized the task-associated theta and beta synchrony between the two hippocampi but also increased synchrony between the medial prefrontal cortex and hippocampus above control levels; (4) the antipsychotic olanzapine was less effective at improving cognitive control and normalizing place avoidance-related inter-hippocampal neural synchrony, although it reduced hyperactivity; and (5) olanzapine caused an abnormal pattern of frequency-independent increases in neural synchrony, in both NVHL and control rats. These data suggest that normalizing aberrant neural synchrony can be beneficial and that drugs targeting the pathophysiology of abnormally coordinated neural activities may be a promising theoretical framework and strategy for developing treatments that improve cognition in neurodevelopmental disorders such as schizophrenia.

No MeSH data available.


Related in: MedlinePlus

Analysis of the multidimensional pattern of synchrony. (A) Thirty-two PLV measures were extracted from the data (8 electrode pairs × 4 frequency bands) and treated as a set of 32-dimensional vectors. PCA analysis was performed on the resulting vector dataset. The first 10 principal components (PC) are shown here (x-axis) with the relative contribution of each measurement (y-axis) indicated by a color code. The PCs tend to group measures with similar properties. As an example, PC #1 corresponds mostly to frequency band-non-specific phase synchrony between the contralateral cortical electrode pairs as well as ipsilateral cortical electrode pairs, which are measures of global cortical phase synchrony. PC #3 corresponds mostly to frequency band-non-specific phase synchrony between the left and right-hippocampi as well as between the left and right prefrontal cortex, which is an estimate of region-specific inter-hemispheric synchrony. PC #6 corresponds to frequency-specific synchrony in the beta, slow gamma, and fast gamma bands between inter-hemispheric neocortical and hippocampal sites. The key measures of synchrony that contributed to each PC are indicated by the dashed boxes. (B) The multidimensional data can be visualized by plotting in the 3-D space of the first three PCs. (C) The cumulative probability of the dataset variance is explained by the PCs. The first six principal components explain ~90% of the dataset variance. (D) The average Euclidean distance between a pair of vectors estimates their distinctiveness. The distances between all pairs of vectors were computed within a treatment group and between all treatment groups and a specific treatment group to estimate similarity/distinctiveness of the treatment groups. The average distances are given to the untreated NVHL group (top row), to the untreated control group (second row), to the ethosuximide-treated NVHL group (third row), and to the olanzapine-treated NVHL group (bottom row).
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Figure 10: Analysis of the multidimensional pattern of synchrony. (A) Thirty-two PLV measures were extracted from the data (8 electrode pairs × 4 frequency bands) and treated as a set of 32-dimensional vectors. PCA analysis was performed on the resulting vector dataset. The first 10 principal components (PC) are shown here (x-axis) with the relative contribution of each measurement (y-axis) indicated by a color code. The PCs tend to group measures with similar properties. As an example, PC #1 corresponds mostly to frequency band-non-specific phase synchrony between the contralateral cortical electrode pairs as well as ipsilateral cortical electrode pairs, which are measures of global cortical phase synchrony. PC #3 corresponds mostly to frequency band-non-specific phase synchrony between the left and right-hippocampi as well as between the left and right prefrontal cortex, which is an estimate of region-specific inter-hemispheric synchrony. PC #6 corresponds to frequency-specific synchrony in the beta, slow gamma, and fast gamma bands between inter-hemispheric neocortical and hippocampal sites. The key measures of synchrony that contributed to each PC are indicated by the dashed boxes. (B) The multidimensional data can be visualized by plotting in the 3-D space of the first three PCs. (C) The cumulative probability of the dataset variance is explained by the PCs. The first six principal components explain ~90% of the dataset variance. (D) The average Euclidean distance between a pair of vectors estimates their distinctiveness. The distances between all pairs of vectors were computed within a treatment group and between all treatment groups and a specific treatment group to estimate similarity/distinctiveness of the treatment groups. The average distances are given to the untreated NVHL group (top row), to the untreated control group (second row), to the ethosuximide-treated NVHL group (third row), and to the olanzapine-treated NVHL group (bottom row).

Mentions: Finally, in the effort to describe neural coordination during the place avoidance task, we examined the full set of 32 synchrony measures (8 electrode pairs × 4 frequency bands) as a pattern to investigate if there were group specific patterns of synchrony (Figure 10). The 32-dimensional space defined by the synchrony vectors (Figure 10A) was reduced to a 3-dimensional space to visualize the data using the first three principal components (Figure 10B). The data formed several clusters instead of filling the parameter space, which suggests neural activity may preferentially occupy preferred locales of this parameter state space. The untreated NVHL and control animals appeared to form two clusters. The ethosuximide and olanzapine-treated groups occupied distinct regions of the space away from the untreated groups. To estimate how distinct the groups might be, we computed the average distance amongst all pairs of vectors within a treatment group. The first six principal components accounted for over 90% of the variance in the data set (Figure 10C), so we computed the pair-wise distances as the 6-D Euclidean distance. The average distance from the untreated NVHL group was significantly greater for each group than it was for the vectors in the untreated NVHL group (Figure 10D). Similarly, the distances from the untreated control vectors were significantly greater for all other groups except the control group treated with ethosuximide, suggesting that ethosuximide did not significantly change control synchrony patterns. Because place avoidance behavior in the NVHL group was improved by ethosuximide, we estimated the distance between this group and the others. The distance to the untreated control group was no different than the distance within the NVHL-ethosuximide group, suggesting that the two groups were relatively similar. The complementary estimate of distance, this time to the olanzapine–NVHL group had a different answer. All groups had greater distances to the olanzapine–NVHL group than the distances amongst the group itself, consistent with the synchrony pattern caused by olanzapine being unique, rather than normalizing.


Targeting Neural Synchrony Deficits is Sufficient to Improve Cognition in a Schizophrenia-Related Neurodevelopmental Model.

Lee H, Dvorak D, Fenton AA - Front Psychiatry (2014)

Analysis of the multidimensional pattern of synchrony. (A) Thirty-two PLV measures were extracted from the data (8 electrode pairs × 4 frequency bands) and treated as a set of 32-dimensional vectors. PCA analysis was performed on the resulting vector dataset. The first 10 principal components (PC) are shown here (x-axis) with the relative contribution of each measurement (y-axis) indicated by a color code. The PCs tend to group measures with similar properties. As an example, PC #1 corresponds mostly to frequency band-non-specific phase synchrony between the contralateral cortical electrode pairs as well as ipsilateral cortical electrode pairs, which are measures of global cortical phase synchrony. PC #3 corresponds mostly to frequency band-non-specific phase synchrony between the left and right-hippocampi as well as between the left and right prefrontal cortex, which is an estimate of region-specific inter-hemispheric synchrony. PC #6 corresponds to frequency-specific synchrony in the beta, slow gamma, and fast gamma bands between inter-hemispheric neocortical and hippocampal sites. The key measures of synchrony that contributed to each PC are indicated by the dashed boxes. (B) The multidimensional data can be visualized by plotting in the 3-D space of the first three PCs. (C) The cumulative probability of the dataset variance is explained by the PCs. The first six principal components explain ~90% of the dataset variance. (D) The average Euclidean distance between a pair of vectors estimates their distinctiveness. The distances between all pairs of vectors were computed within a treatment group and between all treatment groups and a specific treatment group to estimate similarity/distinctiveness of the treatment groups. The average distances are given to the untreated NVHL group (top row), to the untreated control group (second row), to the ethosuximide-treated NVHL group (third row), and to the olanzapine-treated NVHL group (bottom row).
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Related In: Results  -  Collection

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Figure 10: Analysis of the multidimensional pattern of synchrony. (A) Thirty-two PLV measures were extracted from the data (8 electrode pairs × 4 frequency bands) and treated as a set of 32-dimensional vectors. PCA analysis was performed on the resulting vector dataset. The first 10 principal components (PC) are shown here (x-axis) with the relative contribution of each measurement (y-axis) indicated by a color code. The PCs tend to group measures with similar properties. As an example, PC #1 corresponds mostly to frequency band-non-specific phase synchrony between the contralateral cortical electrode pairs as well as ipsilateral cortical electrode pairs, which are measures of global cortical phase synchrony. PC #3 corresponds mostly to frequency band-non-specific phase synchrony between the left and right-hippocampi as well as between the left and right prefrontal cortex, which is an estimate of region-specific inter-hemispheric synchrony. PC #6 corresponds to frequency-specific synchrony in the beta, slow gamma, and fast gamma bands between inter-hemispheric neocortical and hippocampal sites. The key measures of synchrony that contributed to each PC are indicated by the dashed boxes. (B) The multidimensional data can be visualized by plotting in the 3-D space of the first three PCs. (C) The cumulative probability of the dataset variance is explained by the PCs. The first six principal components explain ~90% of the dataset variance. (D) The average Euclidean distance between a pair of vectors estimates their distinctiveness. The distances between all pairs of vectors were computed within a treatment group and between all treatment groups and a specific treatment group to estimate similarity/distinctiveness of the treatment groups. The average distances are given to the untreated NVHL group (top row), to the untreated control group (second row), to the ethosuximide-treated NVHL group (third row), and to the olanzapine-treated NVHL group (bottom row).
Mentions: Finally, in the effort to describe neural coordination during the place avoidance task, we examined the full set of 32 synchrony measures (8 electrode pairs × 4 frequency bands) as a pattern to investigate if there were group specific patterns of synchrony (Figure 10). The 32-dimensional space defined by the synchrony vectors (Figure 10A) was reduced to a 3-dimensional space to visualize the data using the first three principal components (Figure 10B). The data formed several clusters instead of filling the parameter space, which suggests neural activity may preferentially occupy preferred locales of this parameter state space. The untreated NVHL and control animals appeared to form two clusters. The ethosuximide and olanzapine-treated groups occupied distinct regions of the space away from the untreated groups. To estimate how distinct the groups might be, we computed the average distance amongst all pairs of vectors within a treatment group. The first six principal components accounted for over 90% of the variance in the data set (Figure 10C), so we computed the pair-wise distances as the 6-D Euclidean distance. The average distance from the untreated NVHL group was significantly greater for each group than it was for the vectors in the untreated NVHL group (Figure 10D). Similarly, the distances from the untreated control vectors were significantly greater for all other groups except the control group treated with ethosuximide, suggesting that ethosuximide did not significantly change control synchrony patterns. Because place avoidance behavior in the NVHL group was improved by ethosuximide, we estimated the distance between this group and the others. The distance to the untreated control group was no different than the distance within the NVHL-ethosuximide group, suggesting that the two groups were relatively similar. The complementary estimate of distance, this time to the olanzapine–NVHL group had a different answer. All groups had greater distances to the olanzapine–NVHL group than the distances amongst the group itself, consistent with the synchrony pattern caused by olanzapine being unique, rather than normalizing.

Bottom Line: We have proposed a "discoordination" hypothesis that cognitive impairment results from aberrant coordination of neural activity.We report that: (1) inter-hippocampal synchrony in the theta and beta bands is correlated with active place avoidance performance; (2) the anticonvulsant ethosuximide attenuated the abnormal spike-wave activity, improved cognitive control, and reduced hyperlocomotion; (3) ethosuximide not only normalized the task-associated theta and beta synchrony between the two hippocampi but also increased synchrony between the medial prefrontal cortex and hippocampus above control levels; (4) the antipsychotic olanzapine was less effective at improving cognitive control and normalizing place avoidance-related inter-hippocampal neural synchrony, although it reduced hyperactivity; and (5) olanzapine caused an abnormal pattern of frequency-independent increases in neural synchrony, in both NVHL and control rats.These data suggest that normalizing aberrant neural synchrony can be beneficial and that drugs targeting the pathophysiology of abnormally coordinated neural activities may be a promising theoretical framework and strategy for developing treatments that improve cognition in neurodevelopmental disorders such as schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Neural and Behavioral Science, Downstate Medical Center, State University of NewYork , Brooklyn, NY , USA.

ABSTRACT
Cognitive symptoms are core features of mental disorders but procognitive treatments are limited. We have proposed a "discoordination" hypothesis that cognitive impairment results from aberrant coordination of neural activity. We reported that neonatal ventral hippocampus lesion (NVHL) rats, an established neurodevelopmental model of schizophrenia, have abnormal neural synchrony and cognitive deficits in the active place avoidance task. During stillness, we observed that cortical local field potentials sometimes resembled epileptiform spike-wave discharges with higher prevalence in NVHL rats, indicating abnormal neural synchrony due perhaps to imbalanced excitation-inhibition coupling. Here, within the context of the hypothesis, we investigated whether attenuating abnormal neural synchrony will improve cognition in NVHL rats. We report that: (1) inter-hippocampal synchrony in the theta and beta bands is correlated with active place avoidance performance; (2) the anticonvulsant ethosuximide attenuated the abnormal spike-wave activity, improved cognitive control, and reduced hyperlocomotion; (3) ethosuximide not only normalized the task-associated theta and beta synchrony between the two hippocampi but also increased synchrony between the medial prefrontal cortex and hippocampus above control levels; (4) the antipsychotic olanzapine was less effective at improving cognitive control and normalizing place avoidance-related inter-hippocampal neural synchrony, although it reduced hyperactivity; and (5) olanzapine caused an abnormal pattern of frequency-independent increases in neural synchrony, in both NVHL and control rats. These data suggest that normalizing aberrant neural synchrony can be beneficial and that drugs targeting the pathophysiology of abnormally coordinated neural activities may be a promising theoretical framework and strategy for developing treatments that improve cognition in neurodevelopmental disorders such as schizophrenia.

No MeSH data available.


Related in: MedlinePlus