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Article ; Online: Circuits and brain rhythms in schizophrenia: a wealth of convergent targets.

Whittington, Miles A / Roopun, Anita K / Traub, Roger D / Davies, Ceri H

2011 Volume 11, Issue 5, Page(s) 508–514

Abstract: Few common neurological illnesses trace back to single molecular disturbances. Many disparate putative causes may co-associate with a single disease state. However, uncovering functional, hierarchical networks of underlying mechanisms can provide a ... ...

Abstract	Few common neurological illnesses trace back to single molecular disturbances. Many disparate putative causes may co-associate with a single disease state. However, uncovering functional, hierarchical networks of underlying mechanisms can provide a framework in which many primary pathologies converge on more complex, single higher level correlates of disease. This article focuses on cognitive deficits associated with schizophrenia to illustrate: a) How non-invasive EEG biomarkers of cognitive function constitute such a 'higher level correlate' of underlying pathologies. b) How derangement of multiple, cell-specific, molecular processes can converge on such EEG-visible, correlates of disrupted cognitive function. This approach suggests that evidence-based design of multi-target therapies may take advantage of hierarchical patterns of convergence to improve both efficacy and selectivity of disease-intervention.
MeSH term(s)	Animals ; Antipsychotic Agents/therapeutic use ; Brain/drug effects ; Brain/physiopathology ; Brain Waves/drug effects ; Brain Waves/physiology ; Cognition Disorders/drug therapy ; Cognition Disorders/physiopathology ; Electroencephalography ; Humans ; Interneurons/drug effects ; Interneurons/physiology ; Schizophrenia/drug therapy ; Schizophrenia/physiopathology
Chemical Substances	Antipsychotic Agents
Language	English
Publishing date	2011-05-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2011.04.010
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Article: Region-specific changes in gamma and beta2 rhythms in NMDA receptor dysfunction models of schizophrenia.

Roopun, Anita K / Cunningham, Mark O / Racca, Claudia / Alter, Kai / Traub, Roger D / Whittington, Miles A

Schizophrenia bulletin

2008 Volume 34, Issue 5, Page(s) 962–973

Abstract: Cognitive disruption in schizophrenia is associated with altered patterns of spatiotemporal interaction associated with multiple electroencephalogram (EEG) frequency bands in cortex. In particular, changes in the generation of gamma (30-80 Hz) and beta2 ( ...

Abstract	Cognitive disruption in schizophrenia is associated with altered patterns of spatiotemporal interaction associated with multiple electroencephalogram (EEG) frequency bands in cortex. In particular, changes in the generation of gamma (30-80 Hz) and beta2 (20-29 Hz) rhythms correlate with observed deficits in communication between different cortical areas. Aspects of these changes can be reproduced in animal models, most notably those involving acute or chronic reduction in glutamatergic synaptic communication mediated by N-methyl D-aspartate (NMDA) receptors. In vitro electrophysiological and immunocytochemical approaches afforded by such animal models continue to reveal a great deal about the mechanisms underlying EEG rhythm generation and are beginning to uncover which basic molecular, cellular, and network phenomena may underlie their disruption in schizophrenia. Here we briefly review the evidence for changes in gamma-aminobutyric acidergic (GABAergic) and glutamatergic function and address the problem of region specificity of changes with quantitative comparisons of effects of ketamine on gamma and beta2 rhythms in vitro. We conclude, from available evidence, that many observed changes in markers for GABAergic function in schizophrenia may be secondary to deficits in NMDA receptor-mediated excitatory synaptic activity. Furthermore, the broad range of changes in cortical dynamics seen in schizophrenia -- with contrasting effects seen in different brain regions and for different frequency bands -- may be more directly attributable to underlying deficits in glutamatergic neuronal communication rather than GABAergic inhibition alone.
MeSH term(s)	Electroencephalography ; Humans ; Receptors, GABA-A/physiology ; Receptors, N-Methyl-D-Aspartate/physiology ; Schizophrenia/diagnosis ; Schizophrenia/physiopathology ; Signal Transduction
Chemical Substances	Receptors, GABA-A ; Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2008-06-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	439173-1
ISSN	1745-1701 ; 0586-7614
ISSN (online)	1745-1701
ISSN	0586-7614
DOI	10.1093/schbul/sbn059
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Article ; Online: Dual γ rhythm generators control interlaminar synchrony in auditory cortex.

Ainsworth, Matthew / Lee, Shane / Cunningham, Mark O / Roopun, Anita K / Traub, Roger D / Kopell, Nancy J / Whittington, Miles A

The Journal of neuroscience : the official journal of the Society for Neuroscience

2011 Volume 31, Issue 47, Page(s) 17040–17051

Abstract: Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought ... ...

Abstract	Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30-45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50-80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases.
MeSH term(s)	Animals ; Auditory Cortex/physiology ; Brain Waves/physiology ; Electroencephalography/methods ; Electroencephalography Phase Synchronization/physiology ; Excitatory Postsynaptic Potentials/physiology ; Male ; Rats ; Rats, Wistar
Language	English
Publishing date	2011-11-22
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2209-11.2011
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Article: Circuits and brain rhythms in schizophrenia: a wealth of convergent targets

Whittington, Miles A / Roopun, Anita K / Traub, Roger D / Davies, Ceri H

Current opinion in pharmacology. 2011 Oct., v. 11, no. 5

2011

Abstract	Few common neurological illnesses trace back to single molecular disturbances. Many disparate putative causes may co-associate with a single disease state. However, uncovering functional, hierarchical networks of underlying mechanisms can provide a framework in which many primary pathologies converge on more complex, single higher level correlates of disease. This article focuses on cognitive deficits associated with schizophrenia to illustrate: a) How non-invasive EEG biomarkers of cognitive function constitute such a ‘higher level correlate’ of underlying pathologies. b) How derangement of multiple, cell-specific, molecular processes can converge on such EEG-visible, correlates of disrupted cognitive function. This approach suggests that evidence-based design of multi-target therapies may take advantage of hierarchical patterns of convergence to improve both efficacy and selectivity of disease-intervention.
Keywords	biomarkers ; brain waves ; cognition ; schizophrenia
Language	English
Dates of publication	2011-10
Size	p. 508-514.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2011.04.010
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Cholinergic neuromodulation controls directed temporal communication in neocortex in vitro.

Roopun, Anita K / Lebeau, Fiona E N / Rammell, James / Cunningham, Mark O / Traub, Roger D / Whittington, Miles A

Frontiers in neural circuits

2010 Volume 4, Page(s) 8

Abstract: Acetylcholine is the primary neuromodulator involved in cortical arousal in mammals. Cholinergic modulation is involved in conscious awareness, memory formation and attention - processes that involve intercommunication between different cortical regions. ...

Abstract	Acetylcholine is the primary neuromodulator involved in cortical arousal in mammals. Cholinergic modulation is involved in conscious awareness, memory formation and attention - processes that involve intercommunication between different cortical regions. Such communication is achieved in part through temporal structuring of neuronal activity by population rhythms, particularly in the beta and gamma frequency ranges (12-80 Hz). Here we demonstrate, using in vitro and in silico models, that spectrally identical patterns of beta2 and gamma rhythms are generated in primary sensory areas and polymodal association areas by fundamentally different local circuit mechanisms: Glutamatergic excitation induced beta2 frequency population rhythms only in layer 5 association cortex whereas cholinergic neuromodulation induced this rhythm only in layer 5 primary sensory cortex. This region-specific sensitivity of local circuits to cholinergic modulation allowed for control of the extent of cortical temporal interactions. Furthermore, the contrasting mechanisms underlying these beta2 rhythms produced a high degree of directionality, favouring an influence of association cortex over primary auditory cortex.
Language	English
Publishing date	2010-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452968-0
ISSN	1662-5110 ; 1662-5110
ISSN (online)	1662-5110
ISSN	1662-5110
DOI	10.3389/fncir.2010.00008
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Temporal Interactions between Cortical Rhythms.

Roopun, Anita K / Kramer, Mark A / Carracedo, Lucy M / Kaiser, Marcus / Davies, Ceri H / Traub, Roger D / Kopell, Nancy J / Whittington, Miles A

Frontiers in neuroscience

2008 Volume 2, Issue 2, Page(s) 145–154

Abstract: Multiple local neuronal circuits support different, discrete frequencies of network rhythm in neocortex. Relationships between different frequencies correspond to mechanisms designed to minimise interference, couple activity via stable phase interactions, ...

Abstract	Multiple local neuronal circuits support different, discrete frequencies of network rhythm in neocortex. Relationships between different frequencies correspond to mechanisms designed to minimise interference, couple activity via stable phase interactions, and control the amplitude of one frequency relative to the phase of another. These mechanisms are proposed to form a framework for spectral information processing. Individual local circuits can also transform their frequency through changes in intrinsic neuronal properties and interactions with other oscillating microcircuits. Here we discuss a frequency transformation in which activity in two co-active local circuits may combine sequentially to generate a third frequency whose period is the concatenation sum of the original two. With such an interaction, the intrinsic periodicity in each component local circuit is preserved - alternate, single periods of each original rhythm form one period of a new frequency - suggesting a robust mechanism for combining information processed on multiple concurrent spatiotemporal scales.
Language	English
Publishing date	2008-12-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-453X
ISSN (online)	1662-453X
ISSN	1662-453X
DOI	10.3389/neuro.01.034.2008
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Article ; Online: Period concatenation underlies interactions between gamma and beta rhythms in neocortex.

Roopun, Anita K / Kramer, Mark A / Carracedo, Lucy M / Kaiser, Marcus / Davies, Ceri H / Traub, Roger D / Kopell, Nancy J / Whittington, Miles A

Frontiers in cellular neuroscience

2008 Volume 2, Page(s) 1

Abstract: The neocortex generates rhythmic electrical activity over a frequency range covering many decades. Specific cognitive and motor states are associated with oscillations in discrete frequency bands within this range, but it is not known whether ... ...

Abstract	The neocortex generates rhythmic electrical activity over a frequency range covering many decades. Specific cognitive and motor states are associated with oscillations in discrete frequency bands within this range, but it is not known whether interactions and transitions between distinct frequencies are of functional importance. When coexpressed rhythms have frequencies that differ by a factor of two or more interactions can be seen in terms of phase synchronization. Larger frequency differences can result in interactions in the form of nesting of faster frequencies within slower ones by a process of amplitude modulation. It is not known how coexpressed rhythms, whose frequencies differ by less than a factor of two may interact. Here we show that two frequencies (gamma - 40 Hz and beta2 - 25 Hz), coexpressed in superficial and deep cortical laminae with low temporal interaction, can combine to generate a third frequency (beta1 - 15 Hz) showing strong temporal interaction. The process occurs via period concatenation, with basic rhythm-generating microcircuits underlying gamma and beta2 rhythms forming the building blocks of the beta1 rhythm by a process of addition. The mean ratio of adjacent frequency components was a constant - approximately the golden mean - which served to both minimize temporal interactions, and permit multiple transitions, between frequencies. The resulting temporal landscape may provide a framework for multiplexing - parallel information processing on multiple temporal scales.
Language	English
Publishing date	2008-04-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102 ; 1662-5102
ISSN (online)	1662-5102
ISSN	1662-5102
DOI	10.3389/neuro.03.001.2008
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Article ; Online: NMDA receptor-dependent switching between different gamma rhythm-generating microcircuits in entorhinal cortex.

Middleton, Steven / Jalics, Jozsi / Kispersky, Tilman / Lebeau, Fiona E N / Roopun, Anita K / Kopell, Nancy J / Whittington, Miles A / Cunningham, Mark O

Proceedings of the National Academy of Sciences of the United States of America

2008 Volume 105, Issue 47, Page(s) 18572–18577

Abstract: Local circuits in the medial entorhinal cortex (mEC) and hippocampus generate gamma frequency population rhythms independently. Temporal interaction between these areas at gamma frequencies is implicated in memory-a phenomenon linked to activity of NMDA- ... ...

Abstract	Local circuits in the medial entorhinal cortex (mEC) and hippocampus generate gamma frequency population rhythms independently. Temporal interaction between these areas at gamma frequencies is implicated in memory-a phenomenon linked to activity of NMDA-subtype glutamate receptors. While blockade of NMDA receptors does not affect frequency of gamma rhythms in hippocampus, it exposes a second, lower frequency (25-35 Hz) gamma rhythm in mEC. In experiment and model, NMDA receptor-dependent mEC gamma rhythms were mediated by basket interneurons, but NMDA receptor-independent gamma rhythms were mediated by a novel interneuron subtype-the goblet cell. This cell was distinct from basket cells in morphology, intrinsic membrane properties and synaptic inputs. The two different gamma frequencies matched the different intrinsic frequencies in hippocampal areas CA3 and CA1, suggesting that NMDA receptor activation may control the nature of temporal interactions between mEC and hippocampus, thus influencing the pathway for information transfer between the two regions.
MeSH term(s)	Animals ; Entorhinal Cortex/drug effects ; Entorhinal Cortex/physiology ; Ketamine/pharmacology ; Memory ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/physiology
Chemical Substances	Receptors, N-Methyl-D-Aspartate ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2008-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0809302105
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Article ; Online: Rhythm generation through period concatenation in rat somatosensory cortex.

Kramer, Mark A / Roopun, Anita K / Carracedo, Lucy M / Traub, Roger D / Whittington, Miles A / Kopell, Nancy J

PLoS computational biology

2008 Volume 4, Issue 9, Page(s) e1000169

Abstract: Rhythmic voltage oscillations resulting from the summed activity of neuronal populations occur in many nervous systems. Contemporary observations suggest that coexistent oscillations interact and, in time, may switch in dominance. We recently reported an ...

Abstract	Rhythmic voltage oscillations resulting from the summed activity of neuronal populations occur in many nervous systems. Contemporary observations suggest that coexistent oscillations interact and, in time, may switch in dominance. We recently reported an example of these interactions recorded from in vitro preparations of rat somatosensory cortex. We found that following an initial interval of coexistent gamma ( approximately 25 ms period) and beta2 ( approximately 40 ms period) rhythms in the superficial and deep cortical layers, respectively, a transition to a synchronous beta1 ( approximately 65 ms period) rhythm in all cortical layers occurred. We proposed that the switch to beta1 activity resulted from the novel mechanism of period concatenation of the faster rhythms: gamma period (25 ms)+beta2 period (40 ms) = beta1 period (65 ms). In this article, we investigate in greater detail the fundamental mechanisms of the beta1 rhythm. To do so we describe additional in vitro experiments that constrain a biologically realistic, yet simplified, computational model of the activity. We use the model to suggest that the dynamic building blocks (or motifs) of the gamma and beta2 rhythms combine to produce a beta1 oscillation that exhibits cross-frequency interactions. Through the combined approach of in vitro experiments and mathematical modeling we isolate the specific components that promote or destroy each rhythm. We propose that mechanisms vital to establishing the beta1 oscillation include strengthened connections between a population of deep layer intrinsically bursting cells and a transition from antidromic to orthodromic spike generation in these cells. We conclude that neural activity in the superficial and deep cortical layers may temporally combine to generate a slower oscillation.
MeSH term(s)	Animals ; Computational Biology ; Electrophysiology ; Excitatory Amino Acid Agonists/administration & dosage ; In Vitro Techniques ; Kainic Acid/administration & dosage ; Male ; Models, Neurological ; Models, Statistical ; Periodicity ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Somatosensory Cortex/anatomy & histology ; Somatosensory Cortex/drug effects ; Somatosensory Cortex/physiology ; Time Factors
Chemical Substances	Excitatory Amino Acid Agonists ; Receptors, N-Methyl-D-Aspartate ; Kainic Acid (SIV03811UC)
Language	English
Publishing date	2008-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1000169
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Article: A beta2-frequency (20-30 Hz) oscillation in nonsynaptic networks of somatosensory cortex.

Roopun, Anita K / Middleton, Steven J / Cunningham, Mark O / LeBeau, Fiona E N / Bibbig, Andrea / Whittington, Miles A / Traub, Roger D

Proceedings of the National Academy of Sciences of the United States of America

2006 Volume 103, Issue 42, Page(s) 15646–15650

Abstract: ... is determined by the M type of K+ current. ...

Abstract	Beta2 frequency (20-30 Hz) oscillations appear over somatosensory and motor cortices in vivo during motor preparation and can be coherent with muscle electrical activity. We describe a beta2 frequency oscillation occurring in vitro in networks of layer V pyramidal cells, the cells of origin of the corticospinal tract. This beta2 oscillation depends on gap junctional coupling, but it survives a cut through layer 4 and, hence, does not depend on apical dendritic electrogenesis. It also survives a blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors or a blockade of GABA(A) receptors that is sufficient to suppress gamma (30-70 Hz) oscillations in superficial cortical layers. The oscillation period is determined by the M type of K+ current.
MeSH term(s)	Action Potentials/physiology ; Animals ; Beta Rhythm ; Excitatory Amino Acid Agonists/metabolism ; Gap Junctions/metabolism ; Kainic Acid/metabolism ; Male ; Nerve Net/physiology ; Neurons/cytology ; Neurons/metabolism ; Rats ; Rats, Wistar ; Receptors, GABA-A/metabolism ; Somatosensory Cortex/anatomy & histology ; Somatosensory Cortex/physiology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
Chemical Substances	Excitatory Amino Acid Agonists ; Receptors, GABA-A ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (77521-29-0) ; Kainic Acid (SIV03811UC)
Language	English
Publishing date	2006-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0607443103
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