Discrete Cortical Areas Research Articles

Early Life Neuroimaging: The Generalizability of Cortical Area Parcellations Across Development.

The cerebral cortex comprises discrete cortical areas that form during development. Accurate area parcellation in neuroimaging studies enhances statistical power and comparability across studies. The formation of cortical areas is influenced by intrinsic embryonic patterning as well as extrinsic inputs, particularly through postnatal exposure. Given the substantial changes in brain volume, microstructure, and functional connectivity during the first years of life, we hypothesized that cortical areas in 1-to-3-year-olds would exhibit major differences from those in neonates and progressively resemble adults as development progresses. Here, we parcellated the cerebral cortex into putative areas using local functional connectivity gradients in 92 toddlers at 2 years old. We demonstrated high reproducibility of these cortical regions across 1-to-3-year-olds in two independent datasets. The area boundaries in 1-to-3-year-olds were more similar to adults than neonates. While the age-specific group parcellation fitted better to the underlying functional connectivity in individuals during the first 3 years, adult area parcellations might still have some utility in developmental studies, especially in children older than 6 years. Additionally, we provided connectivity-based community assignments of the parcels, showing fragmented anterior and posterior components based on the strongest connectivity, yet alignment with adult systems when weaker connectivity was included.

Neural network bases of thematic semantic processing in language production.

Semantic processing is a central component of language and cognition. The anterior temporal lobe is postulated to be a key hub for semantic processing, but the posterior temporoparietal cortex is also involved in thematic associations during language. It is possible that these regions act in concert and depend on an anteroposterior network linking the temporal pole with posterior structures to support thematic semantic processing during language production. We employed connectome-based lesion-symptom mapping to examine the causal relationship between lesioned white matter pathways and thematic processing language deficits among individuals with post-stroke aphasia. Seventy-nine adults with chronic aphasia completed the Philadelphia Naming Test, and semantic errors were coded as either thematic or taxonomic to control for taxonomic errors. Controlling for nonverbal conceptual-semantic knowledge as measured by the Pyramids and Palm Trees Test, lesion size, and the taxonomic error rate, thematic error rate was associated with loss of white matter connections from the temporal pole traversing in peri-Sylvian regions to the posterior cingulate and the insula. These findings support the existence of a distributed network underlying thematic relationship processing in language as opposed to discrete cortical areas.

Altered Patterns of Brain Glucose Metabolism Involve More Extensive and Discrete Cortical Areas in Treatment-resistant Schizophrenia Patients Compared to Responder Patients and Controls: Results From a Head-to-Head 2-[18F]-FDG-PET Study.

Treatment resistant schizophrenia (TRS) affects almost 30% of patients with schizophrenia and has been considered a different phenotype of the disease. In vivo characterization of brain metabolic patterns associated with treatment response could contribute to elucidate the neurobiological underpinnings of TRS. Here, we used 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) to provide the first head-to-head comparative analysis of cerebral glucose metabolism in TRS patients compared to schizophrenia responder patients (nTRS), and controls. Additionally, we investigated, for the first time, the differences between clozapine responders (Clz-R) and non-responders (Clz-nR). 53 participants underwent FDG-PET studies (41 patients and 12 controls). Response to conventional antipsychotics and to clozapine was evaluated using a standardized prospective procedure based on PANSS score changes. Maps of relative brain glucose metabolism were processed for voxel-based analysis using Statistical Parametric Mapping software. Restricted areas of significant bilateral relative hypometabolism in the superior frontal gyrus characterized TRS compared to nTRS. Moreover, reduced parietal and frontal metabolism was associated with high PANSS disorganization factor scores in TRS (P < .001 voxel level uncorrected, P < .05 cluster level FWE-corrected). Only TRS compared to controls showed significant bilateral prefrontal relative hypometabolism, more extensive in CLZ-nR than in CLZ-R (P < .05 voxel level FWE-corrected). Relative significant hypermetabolism was observed in the temporo-occipital regions in TRS compared to nTRS and controls. These data indicate that, in TRS patients, altered metabolism involved discrete brain regions not found affected in nTRS, possibly indicating a more severe disrupted functional brain network associated with disorganization symptoms.

The organization and development of cortical interneuron presynaptic circuits are area specific.

SUMMARYParvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. Despite the considerable differences between areas, individual interneuron subtypes are genetically invariant and are thought to form canonical circuits regardless of which area they are embedded in. Here, we investigate whether this is achieved through selective and systematic variations in their afferent connectivity during development. To this end, we examined the development of their inputs within distinct cortical areas. We find that interneuron afferents show little evidence of being globally stereotyped. Rather, each subtype displays characteristic regional connectivity and distinct developmental dynamics by which this connectivity is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation and in a model of fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the logic by which these circuits are established during development.

The Organization and Development of Cortical Interneuron Presynaptic Circuits is Area Specific

Parvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. However, despite the considerable differences between cortical regions, both of these interneuron subtypes are genetically invariant and are thought to form similar canonical circuits regardless of which cortical region they are imbedded in. Here we investigate the hypothesis that this is achieved through selective and systematic variations in the afferent connectivity of inhibitory interneurons during development. To this end, we examined the development of the inputs impinging upon parvalbumin and somatostatin interneurons within distinct cortical areas. We found that interneuron afferents showed little evidence of being globally stereotyped. Rather, each cell-type displayed characteristic regional connectivity and distinct developmental dynamics by which this is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation or in a model of Fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the region-specific logic by which these circuits are established during brain development.

Elevated expression of endogenous glial cell line-derived neurotrophic factor impairs spatial memory performance and raises inhibitory tone in the hippocampus.

Parvalbumin-positive interneurons (PV+) are a key component of inhibitory networks in the brain and are known to modulate memory and learning by shaping network activity. The mechanisms of PV+ neuron generation and maintenance are not fully understood, yet current evidence suggests that signalling via the glial cell line-derived neurotrophic factor (GDNF) receptor GFRα1 positively modulates the migration and differentiation of PV+ interneurons in the cortex. Whether GDNF also regulates PV+ cells in the hippocampus is currently unknown. In this study, we utilized a Gdnf "hypermorph" mouse model where GDNF is overexpressed from the native gene locus, providing greatly increased spatial and temporal specificity of protein expression over established models of ectopic expression. Gdnfwt/hyper mice demonstrated impairments in long-term memory performance in the Morris water maze test and an increase in inhibitory tone in the hippocampus measured electrophysiologically in acute brain slice preparations. Increased PV+ cell number was confirmed immunohistochemically in the hippocampus and in discrete cortical areas and an increase in epileptic seizure threshold was observed in vivo. The data consolidate prior evidence for the actions of GDNF as a regulator of PV+ cell development in the cortex and demonstrate functional effects upon network excitability via modulation of functional GABAergic signalling and under epileptic challenge.

Bout-associated intrinsic functional network changes in cluster headache: A longitudinal resting-state functional MRI study.

Background Previous imaging studies on the pathogenesis of cluster headache (CH) have implicated the hypothalamus and multiple brain networks. However, very little is known regarding dynamic bout-associated, large-scale resting state functional network changes related to CH. Methods Resting-state functional magnetic resonance imaging data were obtained from CH patients and matched controls. Data were analyzed using independent component analysis for exploratory assessment of the changes in intrinsic brain networks and their relationship between in-bout and out-of-bout periods, as well as correlations with clinical observations. Results Compared to healthy controls, CH patients had functional connectivity (FC) changes in the temporal, frontal, salience, default mode, somatosensory, dorsal attention, and visual networks, independent of bout period. Compared to out-of-bout scans, in-bout scans showed altered FC in the frontal and dorsal attention networks. Lower frontal network FC correlated with longer duration of CH. Conclusions The present findings suggest that episodic CH with dynamic bout period shifts may involve bout-associated FC changes in multiple discrete cortical areas within networks outside traditional pain processing areas. Dynamic changes in FC in frontal and dorsal attention networks between bout periods could be important for understanding episodic CH pathophysiology.

Resting state functional connectivity of the subthalamic nucleus in Parkinson's disease assessed using arterial spin-labeled perfusion fMRI.

Neurophysiological changes within the cortico-basal ganglia-thalamocortical circuits appear to be a characteristic of Parkinson's disease (PD) pathophysiology. The subthalamic nucleus (STN) is one of the basal ganglia components showing pathological neural activity patterns in PD. In this study, perfusion imaging data, acquired noninvasively using arterial spin-labeled (ASL) perfusion MRI, were used to assess the resting state functional connectivity (FC) of the STN in 24 early-to-moderate PD patients and 34 age-matched healthy controls, to determine whether altered FC in the very low frequency range of the perfusion time signal occurs as a result of the disease. Our results showed that the healthy STN was functionally connected with other nuclei of the basal ganglia and the thalamus, as well as with discrete cortical areas including the insular cortex and the hippocampus. In PD patients, connectivity of the STN was increased with two cortical areas involved in motor and cognitive processes. These findings suggest that hyperconnectivity of the STN could underlie some of the motor and cognitive deficits often present even at early stages of the disease. The FC measures provided good discrimination between controls and patients, suggesting that ASL-derived FC metrics could be a putative PD biomarker.

Curvature-processing network in macaque visual cortex.

Our visual environment abounds with curved features. Thus, the goal of understanding visual processing should include the processing of curved features. Using functional magnetic resonance imaging in behaving monkeys, we demonstrated a network of cortical areas selective for the processing of curved features. This network includes three distinct hierarchically organized regions within the ventral visual pathway: a posterior curvature-biased patch (PCP) located in the near-foveal representation of dorsal V4, a middle curvature-biased patch (MCP) located on the ventral lip of the posterior superior temporal sulcus (STS) in area TEO, and an anterior curvature-biased patch (ACP) located just below the STS in anterior area TE. Our results further indicate that the processing of curvature becomes increasingly complex from PCP to ACP. The proximity of the curvature-processing network to the well-known face-processing network suggests a possible functional link between them.

Isolated Hand Paralysis Due to Stroke in Precentral Knob Region (P02.191)

Objective: To document a rare presentation of stroke. Background Lhermitte described 9pseudoperipheral palsy9 as a weakness of fingers due to a CNS lesion, now thought to be 1% of all ischaemic strokes. Often misdiagnosed, the opportunities to identify and treat stroke risk factors are missed. Design/Methods: A 62 year-old male presented with difficulty of finger movements and wrist drop of left hand, for two days. Patient had history of hyperlipedemia. On exam, his blood pressure was 195/100mm Hg with normal vitals,left wrist drop, weak finger flexion,abduction and adduction, weak thumb extension flexion and adduction, with brisk left brachioradialis reflex. Rest of the neurological examination was normal. Results: Due to isolated hand weakness, we were tempted to think of peripheral lesion, however due to involvement of muscle supplied by radial, medial and ulner nerve and brisk brachioradialis reflex, MRI brain was done to look for central cause, which showed diffusion positive lesion in mid of the right precentral gyrus suggestive of acute stroke. Patient was managed for acute stroke and was discharged home with mild improvement of weakness. Conclusions: Functional MRI suggests that the w or E shaped area (the precentral knob) on the precentral gyrus in the axial plane is the hand area. Medial portion of the precentral knob representing topographically ulnar-sided fingers may correspond to the borderzone area between the middle cerebral artery (MCA) and the anterior cerebral artery, whereas the lateral portion representing radial-sided fingers is supplied by distal MCA branches. Cortical hand paralysis characteristically cause partial finger paralysis, producing pseudo-ulner or pseudoradicular pattern with difference in the severity of paralysis between the radial side and the ulnar side, important in differentiating cortical hand paralysis from subcortical lesions. Discrete functional cortical areas for each digit exist and are sequentially arranged, with considerable overlap of control of adjacent territory. Disclosure: Dr. Vyas has nothing to disclose. Dr. Staudinger has nothing to disclose. Dr. Hanson has nothing to disclose.

Electrostimulation Mapping of Spatial Neglect

Cortical and subcortical electrostimulation mapping during awake brain surgery for tumor removal is usually used to minimize deficits. To use electrostimulation to study neuronal substrates involved in spatial awareness in humans. Spatial neglect was studied using a line bisection task in combination with electrostimulation mapping of the right hemisphere in 50 cases. Stimulation sites were identified with Talairach coordinates. The behavioral effects induced by stimulation, especially eye movements and deviations from the median, were quantified and compared with preoperative data and a control group. Composite and highly individualized spatial neglect maps were generated. Both rightward and leftward deviations were induced, sometimes in the same patient but for different stimulation sites. Group analysis showed that specific and reproducible line deviations were induced by stimulation of discrete cortical areas located in the posterior part of the right superior and middle temporal gyri, inferior parietal lobe, and inferior postcentral and inferior frontal gyri (P < .05). Fiber tracking identified stimulated subcortical areas important to spare as sections of fronto-occipital and superior longitudinal II fascicles. According to preoperative and postoperative neglect battery tests, the specificity and sensitivity of intraoperative line bisection tests were 94% and 83%, respectively. In humans, discrete cortical areas that are variable in location between individuals but mainly located within the right posterior Sylvian fissure sustain visuospatial attention specifically toward the contralateral or ipsilateral space direction. Line bisection mapping was found to be a reliable method for minimizing spatial neglect caused by brain tumor surgery.

Crossed aphasia elicited by intraoperative cortical and subcortical stimulation in awake patients

Crossed aphasia (aphasia resulting from a right hemispheric lesion among right-handed patients) is rare. The authors describe for the first time transient crossed aphasia elicited by intraoperative electrostimulation of both cortex and white matter pathways in awake patients. Three right-handed adults underwent surgery for a right-sided glioma. Because slight language disorders occurred during partial seizures or were identified on preoperative cognitive assessment, with right activations detected on language functional MR imaging in 1 patient, awake craniotomy was performed using intraoperative cortico-subcortical electrical functional mapping. Transient language disturbances were elicited by stimulating discrete cortical areas (inferior frontal gyrus and posterior part of the superior temporal gyrus) and white matter pathways (inferior frontooccipital fasciculus and arcuate fasciculus). A subtotal resection was achieved in all cases, according to functional boundaries. Postoperatively, 1 patient experienced a transient dysphasia, which resolved after speech rehabilitation, with no permanent deficit. These original findings highlight the possibility of finding crucial cortico-subcortical language networks in the right hemisphere in a subgroup of atypical right-handed patients. These findings provide new insights into the neural basis of language, by underlining the role of the right inferior occipitofrontal fasciculus in semantics and that of the right arcuate fasciculus in phonology, and by supporting the hypothesis of a mirror organization between the right and left hemispheres. The authors suggest that, in right-handed patients, if language disturbances are detected during seizures or on presurgical neuropsychological assessment, especially when right activations are observed on language functional MR imaging, awake craniotomy with intraoperative language mapping should be considered.

An integrated fMRI, SEPs and MEPs approach for assessing functional organization in the malformed sensorimotor cortex

Malformations of cortical development are often accompanied by an abnormal cortical pattern. Due to its propensity to involve discrete cortical areas, polymicrogyria represents an interesting model for assessing the reorganization of cortical function in relation to the disrupted anatomy. Functional MRI, TMS and SEPs can provide a highly complementary, multimodal approach to map noninvasively the functional rearrangement of sensorimotor functions in the polymicrogyric cortex, and to obtain a coherent modelling. We report here an illustrative case which is included in a patients series under study using a block design 3T fMRI, short-latency SEPs as identified on the basis of their latency, polarity, and scalp distribution and an assessment of the area and volume of the motor maps and the relative position of the center of gravity and hot spot. A 15 years old girl, with drug-resistant epilepsy and left perisylvian polymicrogyria that was part of a large epileptogenic network including also the mesial aspect of the left frontal lobe, exhibited a normal distribution of somatomotor responses in the expected anatomic sites, with a dissociation between motor functions, which were slightly impaired in the malformed hemisphere, and bilaterally normal sensory responses. In this patient, a large resection of epileptogenic zone, sparing eloquent areas as previously identified, should be planned in order to improve seizure outcome. An integrated fMRI, TMS and SEP mapping approach helps defining the relationship between epileptogenic zones and somatomotor areas. Studies of greater number of patients will be necessary in order to identify the general rules that determine the functional representation in the malformed cortex.

Regional differential effects of chronic nicotine on brain α4-containing and α6-containing receptors

Chronic nicotine upregulates central nicotinic acetylcholine receptors (nAChRs), a plasticity process thought to contribute to its addictive properties. To analyze this process in vivo, we chronically exposed mice to nicotine using minipump delivering nicotine at concentrations close to those found in tobacco smokers. Binding studies show upregulation of high-affinity nAChRs after 21 days of treatment in cortical areas, caudate putamen, nucleus accumbens, hippocampus, ventral tegmental area, and superior colliculi. No upregulation was observed in thalamus and discrete cortical areas. Using wild type and alpha 6-/- mice, we observed a downregulation of alpha 6*-nAChRs in superior colliculi and no effects in other structures. The complex pattern of upregulation/downregulation observed in this study depends on both nAChR composition and regional distribution.

Alteration of neuronal firing properties after in vivo experience in a FosGFP transgenic mouse.

Identifying the cells and circuits that underlie perception, behavior, and learning is a central goal of contemporary neuroscience. Although techniques such as lesion analysis, functional magnetic resonance imaging, 2-deoxyglucose studies, and induction of gene expression have been helpful in determining the brain areas responsible for particular functions, these methods are technically limited. Currently, there is no method that allows for the identification and electrophysiological characterization of individual neurons that are associated with a particular function in living tissue. We developed a strain of transgenic mice in which the expression of the green fluorescent protein (GFP) is controlled by the promoter of the activity-dependent gene c-fos. These mice enable an in vivo or ex vivo characterization of the cells and synapses that are activated by particular pharmacological and behavioral manipulations. Cortical and subcortical fosGFP expression could be induced in a regionally restricted manner after specific activation of neuronal ensembles. Using the fosGFP mice to identify discrete cortical areas, we found that neurons in sensory-spared areas rapidly regulate action potential threshold and spike frequency to decrease excitability. This method will enhance our ability to study the way neuronal networks are activated and changed by both experience and pharmacological manipulations. In addition, because activated neurons can be functionally characterized, this tool may enable the development of better pharmaceuticals that directly affect the neurons involved in disease states.

Changes in rectal temperature and ECoG spectral power of sensorimotor cortex elicited in conscious rabbits by i.c.v. injection of GABA, GABA(A) and GABA(B) agonists and antagonists.

1. In order to ascertain whether both GABA(A) and GABA(B), or only GABA(B) receptors, directly modulate thermoregulation in conscious rabbits, GABA(A)/GABA(B) agonist and antagonist agents were injected intracerebroventricularly in conscious rabbits while monitoring changes in rectal temperature (RT), gross motor behaviour (GMB) and electrocorticogram (ECoG) power spectra (ps) from sensorimotor cortices. 2. GABA (48 micromol), nipecotic acid (50 nmol), THIP (60 nmol), muscimol (18 nmol) and baclofen (8 nmol) induced hypothermia (-deltaRTmax values of 1.70+/-0.1, 1.4+/-0.2, 1.0+/-0.4, 1.1+/-0.2 and 1.6+/-0.3 degrees C, respectively), accompanied by inhibition of GMB and ECoG synchronization. THIP increased ps at delta frequency band (1.1-3.3 Hz), while GABA, nipecotic acid, muscimol and baclofen did the same at both delta and (4.6-6.5 Hz) frequency bands. ECoG ps changes were concomitant or even preceded hypothermia. 3. Bicuculline (1.8 nmol) induced hyperthermia (deltaRTmax 1.2+/-0.5 degrees C) and slight excitation of GMB, while CGP35348 (1.2 micromol) did not affect RT nor GMB. Both compounds did not affect ECoG ps. 4. Bicuculline potentiated muscimol-induced hypothermia, inhibition of GMB and synchronization of ECoG, while CGP35348 fully antagonized these effects. 5. In conclusion, the present results, while confirming the prevailing role of GABA(B), also outline a direct involvement of GABA(A) receptors in the central mechanisms of thermoregulation. Ascending inhibition towards discrete cortical areas controlling muscular activity and thermogenesis may result from GABA receptor activation in neurones proximal to the ventricles, thus contributing to hypothermia, although hypothermia-induced reduction of neuronal activity of these cortical areas cannot be ruled out.

Auditory thalamic nuclei projections to the temporal cortex in the rat

Thalamocortical projections from the auditory thalamic nuclei were examined systematically in the rat, including those from the dorsal division (MGD) of the medial geniculate body (MG), which were less clearly determined in previous studies. Injections of biocytin confined in each thalamic nucleus revealed characteristic features of projections in terms of cortical areas and layers of termination. In contrast to exclusively selective projections to cortical area Te1 from the ventral division (MGV) of the MG, diffuse and selective terminations were observed in the projections from the dorsal (MGD) and medial divisions (MGM) of the MG and the suprageniculate nucleus (SG). Diffuse termination was continuous in layer I or VI of the temporal cortex, while selective termination was in layers III and IV of discrete cortical areas. In addition to diffuse termination in the upper half of layer I of cortical areas Te1, Te2d and Te3v, the MGD and SG projections formed plexuses of axons selectively in lower layer III and layer IV of Te2d and Te3v. The SG projections targeted further the dorsal bank of the perirhinal cortex (PRh), while the MGD projections targeted in part the ventral fringe of Te1. The MGM projections terminated diffusely in layer VI of Te1 and Te3v, and selectively in lower layer III and layer IV of the rostral part of Te3v. Diffuse projections to layers I and VI from the SG and MGM extended in cortical regions over the dorsal fringe of Te1. Selective dense projections to middle cortical layers of Te2d and Te3v (especially its rostral part) indicate the existence of auditory areas, which could be involved in cross-modal interaction with visual and somatosensory system, respectively. Diffuse projections are supposed to bind information processings in these areas and the primary auditory area (Te1).

Regional Age-Dependent Effects of Hemineodecortication upon Contralateral Neocortical Thickness: Comparison with Other Measures of Cortical Size

This study investigated age-dependent changes in regional neocortical thickness after hemineodecortication in cats and compared the results to previously reported volumetric and cross-sectional data. Subjects sustained hemineodecortication on postnatal days (P) P10, P30, P60 or in adulthood. Neocortical thickness was quantified at 115 sites along 20 stereotaxic coronal anterior-posterior (AP) planes using defined sites of the main cerebral sulci for the measurements. The analysis established significantly lower thickness values for adult-lesioned as compared to (a) P30, P60 and control groups at AP +14, (b) P30 group at 7 planes along a range of AP +9 to AP +3, and (c) P10 and P60 groups at AP +6. Both the P10 and the P30 groups presented a significantly thicker neocortex than controls at select coronal planes clustering behind AP +10 (parietal and temporal cortices). When analyzed by sulcus, results once again reflected significant advantages for the early-lesioned cats with a significantly thicker cortex found at 4 of the 8 sulci examined. Again, significant advantages were also discovered for early-lesion subjects compared with control cats (splenial, cruciate sulci). Overall, the range of significant effects (from AP +14 to AP 0) and the direction of the means suggested that there was a significant, age-dependent (P10–P60), regional sparing of neocortical thickness with a peak effect occurring at P30. We concluded that: (a) there was a regional sparing/increase of neocortical thickness suggesting that discrete cortical areas are selectively involved in the resistance to structural atrophy following hemineodecortication in young cats (P10–P60) and (b) the global loss of neocortex volume found in our previous study was not apparent using the present thickness measurement. It is suggested that both of these measurements must be taken into account when assessing morphological effects upon the neocortex either in human pathology (i.e. hemispherectomy, intractable epilepsy) or in animal models.

The importance of nonlinear dendritic processing in multimodular memory networks

Recent imaging studies testify that objects are stored in the brain in a distributed network of discrete cortical areas. Motivated by these observations, we study a multi-modular associative memory network, whose functional goal is to store patterns of different coding levels, i.e., patterns that vary in the number of modules in which they are encoded. We show that in order to accomplish this task, the synaptic inputs to each neuron should be segregated to intramodular projections whose activations are summed up linearly, and inter-modular projections whose activations are summed up in a nonlinear fashion. This may reflect dendritic processing of distal synaptic connections. Moreover, we find that further hierarchical segregation of inter-modular connections on the dendritic tree improves memory retrieval from partial input cues, and improves resilience of the network to afferent damage.

Morphine disrupts long-range synchrony of gamma oscillations in hippocampal slices.

Oscillations in neuronal population activity within the gamma frequency band (>25 Hz) have been correlated with cognition: Gamma oscillations could bind together features of a sensory stimulus by generating synchrony between discrete cortical areas [Eckhorn, R., Bauer, R., Jordan, W., Brosch, M., Kruse, W., Munk, M. & Reitboeck, H. J. (1989) Biol. Cybern. 60, 121-130; Singer, W. & Gray, C. M. (1995) Annu. Rev. Neurosci. 18, 555-556]. Herein we demonstrate that morphine and beta-endorphin disrupt this long-range synchrony of gamma oscillations while leaving the synchrony of local oscillations relatively intact. The effect is caused by a decrease in type A gamma-aminobutyric acid receptor-mediated inhibition of both excitatory pyramidal cells and inhibitory interneurons. The effects of morphine on gamma oscillations were blocked by mu-opioid receptor antagonists but not by antagonists of delta or kappa receptors. Morphine also produced burst firing in interneurons, because synaptic excitation from pyramidal cells was no longer balanced by synchronous inhibitory postsynaptic potentials. The loss of synchrony of gamma oscillations induced by morphine may constitute one mechanism involved in producing the cognitive deficits that this drug causes clinically.