Abnormalities in thalamo-cortical connections in patients with first-episode schizophrenia: a two-tensor tractography study.

The "cognitive dysmetria" hypothesis suggests that impairments in cognition and behavior in patients with schizophrenia can be explained by disruptions in the cortico-cerebellar-thalamic-cortical circuit. In this study we examine thalamo-cortical connections in patients with first-episode schizophrenia (FESZ). White matter pathways are investigated that connect the thalamus with three frontal cortex regions including the anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), and lateral oribitofrontal cortex (LOFC). We use a novel method of two-tensor tractography in 26 patients with FESZ compared to 31 healthy controls (HC), who did not differ on age, sex, or education. Dependent measures were fractional anisotropy (FA), Axial Diffusivity (AD), and Radial Diffusivity (RD). Subjects were also assessed using clinical functioning measures including the Global Assessment of Functioning (GAF) Scale, the Global Social Functioning Scale (GF: Social), and the Global Role Functioning Scale (GF: Role). FESZ patients showed decreased FA in the right thalamus-right ACC and right-thalamus-right LOFC pathways compared to healthy controls (HCs). In the right thalamus-right VLPFC tract, we found decreased FA and increased RD in the FESZ group compared to HCs. After correcting for multiple comparisons, reductions in FA in the right thalamus- right ACC and the right thalamus- right VLPC tracts remained significant. Moreover, reductions in FA were significantly associated with lower global functioning scores as well as lower social and role functioning scores. We report the first diffusion tensor imaging study of white matter pathways connecting the thalamus to three frontal regions. Findings of white matter alterations and clinical associations in the thalamic-cortical component of the cortico-cerebellar-thalamic-cortical circuit in patients with FESZ support the cognitive dysmetria hypothesis and further suggest the possible involvement of myelin sheath pathology and axonal membrane disruption in the pathogenesis of the disorder.

Sensory-based and higher-order operations contribute to abnormal emotional prosody processing in schizophrenia: an electrophysiological investigation.

BACKGROUND: Schizophrenia is characterized by deficits in emotional prosody (EP) perception. However, it is not clear which stages of processing prosody are abnormal and whether the presence of semantic content contributes to the abnormality. This study aimed to examine event-related potential (ERP) correlates of EP processing in 15 chronic schizophrenia individuals and 15 healthy controls. METHOD: A total of 114 sentences with neutral semantic content [sentences with semantic content (SSC) condition] were generated by a female speaker (38 with happy, 38 with angry, and 38 with neutral intonation). The same sentences were synthesized and presented in the 'pure prosody' sentences (PPS) condition where semantic content was unintelligible. RESULTS: Group differences were observed for N100 and P200 amplitude: patients were characterized by more negative N100 for SSC, and more positive P200 for angry and happy SSC and happy PPS. Correlations were found between delusions and P200 amplitude for happy SSC and PPS. Higher error rates in the recognition of EP were also observed in schizophrenia: higher error rates in neutral SSC were associated with reduced N100, and higher error rates in angry SSC were associated with reduced P200. CONCLUSIONS: These results indicate that abnormalities in prosody processing occur at the three stages of EP processing, and are enhanced in SSC. Correlations between P200 amplitude for happy prosody and delusions suggest a role that abnormalities in the processing of emotionally salient acoustic cues may play in schizophrenia symptomatology. Correlations between ERP and behavioral data point to a relationship between early sensory abnormalities and prosody recognition in schizophrenia.

Single-trial coupling of the gamma-band response and the corresponding BOLD signal.

Oscillations in the gamma-band frequency range have been described to be more closely connected to hemodynamic changes as assessed with functional magnetic resonance imaging (fMRI) than other aspects of neuronal activity. In addition, gamma-band oscillations have attracted much interest during the last few years since they are thought to play a crucial role in many aspects of brain function related to perception and cognition. It was the aim of the present simultaneous EEG-fMRI study to identify brain regions specifically involved in the generation of the auditory gamma-band response (GBR) using single-trial coupling of EEG and fMRI. Ten healthy subjects participated in this study. Three different runs of an auditory choice reaction task with increasing difficulty were performed. Brain activity was recorded simultaneously with high density EEG (61 channels) and fMRI (1.5 T). BOLD correlates of the GBR have been predicted using the single-trial amplitude of the GBR. Reaction times (p<0.001), error rates (p<0.05) and self-ratings of task difficulty and effort demands (p<0.001) were related to the level of difficulty in the task. In addition, we found a significant influence of task difficulty on the amplitude of the GBR at Cz (p<0.05). Using single-trial coupling of EEG and fMRI GBR-specific activations were found only in the auditory cortex, the thalamus and the anterior cingulate cortex (ACC) in the most difficult run. Single-trial coupling might be a useful method in order to increase our knowledge about the functional neuroanatomy of "neural ensembles" coupled by 40 Hz oscillations.

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep-wakefulness: role of delta-subunit containing extrasynaptic GABAA receptors.

Gaboxadol or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP) is a selective agonist for the delta-subunit containing extrasynaptic GABA(A) receptors that will soon enter the U.S. market as a sleep aid [Winsky-Sommerer R, Vyazovskiy VV, Homanics GE, Tobler I (2007) The EEG effects of THIP (gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors. Eur J Neurosci 25:1893-1899]. Numerous studies have shown that systemic administration of THIP reduces wakefulness and increases sleep both in humans and rats [Lancel M, Langebartels A (2000) Gamma-aminobutyric acid(A) (GABA(A)) agonist 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. J Pharmacol Exp Ther 293:1084-1090; Walsh JK, Deacon S, Dijk DJ, Lundahl J (2007) The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 30:593-602]. However, it is yet unclear where in the brain THIP acts to promote sleep. Since the perifornical lateral hypothalamus (PFH) contains orexin neurons and orexin neurons are critical for maintenance of arousal [McCarley RW (2007) Neurobiology of rapid eye movement (REM) and NREM sleep. Sleep Med 8:302-330], we hypothesized that THIP may act on PFH neurons to promote sleep. To test our hypothesis, we used reverse microdialysis to perfuse THIP unilaterally into the PFH and studied its effects on sleep-wakefulness during the light period in freely behaving rats. Microdialysis perfusion of THIP (100 microM) into the PFH produced a significant reduction in wakefulness with a concomitant increase in non-rapid eye movement or slow wave sleep as compared with artificial cerebrospinal fluid perfusion. REM sleep was unaffected. This is the first study implicating the delta-subunit containing extrasynaptic GABA(A) receptors in PFH in control of sleep-wakefulness in freely behaving rats.

A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.

OBJECTIVE: Previous research has noted functional and structural temporal lobe abnormalities in schizophrenia that relate to symptoms such as auditory hallucinations and thought disorder. The goal of the study was to determine whether the functional abnormalities are present in schizophrenia at early stages of auditory processing. METHOD: Functional magnetic resonance imaging activity was examined during the presentation of the mismatch stimuli, which are deviant tones embedded in a series of standard tones. The mismatch stimuli are used to elicit the mismatch negativity, an early auditory event-related potential. Ten patients with schizophrenia and 10 comparison subjects were presented the mismatch stimuli condition and a control condition in which only one tone was presented repeatedly. RESULTS: The superior temporal gyrus showed the most prevalent and consistent activation. The superior temporal gyrus showed less activation in the schizophrenic subjects than in the comparison subjects only during the mismatch stimuli condition. CONCLUSIONS: This result is consistent with those of mismatch negativity event-related potential studies and suggests that early auditory processing is abnormal in chronic schizophrenia.

A quantitative MR measure of the fornix in schizophrenia.

Some cognitive disturbances accompanying schizophrenia may be due to abnormalities in the thalamus and components of the limbic system. The fornix is an important white-matter relay pathway connecting these structures and is likely to be affected in schizophrenia as well.Magnetic resonance images of the fornix were analyzed in 15 schizophrenic patients and 15 matched comparison group subjects. Fornix volume was compared between the two groups and was also correlated with the volumes of other neuroanatomical structures, as well as with illness presentation, clinical status, and cognitive/psychological measures. There was no significant difference in fornix volume between the two groups. Of note, fornix volume correlated significantly with the volumes of the hippocampus, parahippocampus, and the superior temporal gyrus in the schizophrenic subjects, but not in the controls. Moreover, the correlation between fornix and parahippocampal gyrus volumes differed significantly between the two groups. No association was found between fornix volume and illness presentation or between fornix and cognitive/clinical measures.Results suggest that there are no marked changes in fornix volume in schizophrenia by MRI. The fornix, however, may be part of a network of structures affected in schizophrenia, as indicated by correlated volumetric changes.

Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.

BACKGROUND: Basic science studies at the neuronal systems level have indicated that gamma-range (30-50 Hz) neural synchronization may be a key mechanism of information processing in neural networks, reflecting integration of various features of an object. Furthermore, gamma-range synchronization is thought to depend on the glutamatergically mediated interplay between excitatory projection neurons and inhibitory neurons utilizing gamma-aminobutyric acid (GABA), which postmortem studies suggest may be abnormal in schizophrenia. We therefore tested whether auditory neural networks in patients with schizophrenia could support gamma-range synchronization. METHODS: Synchronization of the electroencephalogram (EEG) to different rates (20-40 Hz) of auditory stimulation was recorded from 15 patients with schizophrenia and 15 sex-, age-, and handedness-matched control subjects. The EEG power at each stimulation frequency was compared between groups. The time course of the phase relationship between each stimulus and EEG peak was also evaluated for gamma-range (40 Hz) stimulation. RESULTS: Schizophrenic patients showed reduced EEG power at 40 Hz, but not at lower frequencies of stimulation. In addition, schizophrenic patients showed delayed onset of phase synchronization and delayed desynchronization to the click train. CONCLUSIONS: These data provide new information on selective deficits in early-stage sensory processing in schizophrenia, a failure to support the entrainment of intrinsic gamma-frequency oscillators. The reduced EEG power at 40 Hz in schizophrenic patients may reflect a dysfunction of the recurrent inhibitory drive on auditory neural networks.

Choline acetyltransferase expression during periods of behavioral activity and across natural sleep-wake states in the basal forebrain.

The present study examined whether the expression of the messenger RNA encoding the protein responsible for acetylcholine synthesis is associated with sleep-wakefulness. Choline acetyltransferase messenger RNA levels were analysed using a semi-quantitative assay in which reverse transcription was coupled to complementary DNA amplification using the polymerase chain reaction. To examine the relationship between steady-state messenger RNA and behavioral activity, rats were killed during the day (4.00 p.m.) or night (4.00 a.m.), and tissue from the vertical and horizontal limbs of the diagonal bands of Broca was analysed. Choline acetyltransferase messenger RNA levels were higher during the day than during the night. The second study examined more closely the association between choline acetyltransferase messenger RNA levels and individual bouts of wakefulness, slow-wave sleep or rapid eye movement sleep. Choline acetyltransferase messenger RNA levels were low during wakefulness, intermediate in slow-wave sleep and high during rapid eye movement sleep. In contrast, protein activity, measured at a projection site of cholinergic neurons of the basal forebrain, was higher during wakefulness than during sleep. These findings suggest that choline acetyltransferase protein and messenger RNA levels exhibit an inverse relationship during sleep and wakefulness. The increased messenger RNA expression during sleep is consistent with a restorative function of sleep.

REM sleep enhancement and behavioral cataplexy following orexin (hypocretin)-II receptor antisense perfusion in the pontine reticular formation.

Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are involved in the neural control of REM sleep, including the locus coeruleus, the dorsal raphe nucleus, the cholinergic zone of the mesopontine tegmentum, and the pontine reticular formation (PRF). Orexin knockout mice exhibit narcolepsy/cataplexy, and a mutant and defective gene for the orexin type II receptor is present in dogs with an inherited form of narcolepsy/cataplexy. However, the physiological systems mediating these effects have not been described. We reasoned that, since the effector neurons for the majority of REM sleep signs, including muscle atonia, were located in the PRF, this region was likely implicated in the production of these orexin-related abnormalities. To test this possibility, we used microdialysis perfusion of orexin type II receptor antisense in the PRF of rats. Ten to 24 hours after antisense perfusion, REM sleep increased two- to three-fold during both the light period (quiescent phase) and the dark period (active phase), and infrared video showed episodes of behavioral cataplexy. Moreover, preliminary data indicated no REM-related effects following perfusion with nonsense DNA, or when perfusion sites were outside the PRF. More work is needed to provide precise localization of the most effective site of orexin-induced inhibition of REM sleep phenomena.

Auditory mismatch negativity in schizophrenia: topographic evaluation with a high-density recording montage.

OBJECTIVE: The mismatch negativity, a negative component in the auditory event-related potential, is thought to index automatic processes involved in sensory or echoic memory. The authors' goal in this study was to examine the topography of auditory mismatch negativity in schizophrenia with a high-density, 64-channel recording montage. METHOD: Mismatch negativity topography was evaluated in 23 right-handed male patients with schizophrenia who were receiving medication and in 23 nonschizophrenic comparison subjects who were matched in age, handedness, and parental socioeconomic status. The Positive and Negative Syndrome Scale was used to measure psychiatric symptoms. RESULTS: Mismatch negativity amplitude was reduced in the patients with schizophrenia. They showed a greater left-less-than-right asymmetry than comparison subjects at homotopic electrode pairs near the parietotemporal junction. There were correlations between mismatch negativity amplitude and hallucinations at left frontal electrodes and between mismatch negativity amplitude and passive-apathetic social withdrawal at left and right frontal electrodes. CONCLUSIONS: Mismatch negativity was reduced in schizophrenia, especially in the left hemisphere. This finding is consistent with abnormalities of primary or adjacent auditory cortex involved in auditory sensory or echoic memory.

Volumetric evaluation of the thalamus in schizophrenic male patients using magnetic resonance imaging.

BACKGROUND: The thalamus, an important subcortical brain region connecting limbic and prefrontal cortices, has a significant role in sensory and cortical processing. Although inconsistently, previous studies have demonstrated neuroanatomical abnormalities in the thalamus of schizophrenic patients. METHODS: This structural magnetic resonance imaging study, based on segmentation of contiguous coronal 1.5-mm images, compared thalamic brain volumes of 15 chronic, male schizophrenic patients with 15 normal controls matched on age, sex, handedness, and parental socioeconomic status. RESULTS: There were no significant differences between patients and controls in thalamic volumes, right or left, adjusted for total brain volume; however, there were significantly different correlations of thalamic volumes with prefrontal white matter and lateral ventricles among patients, but not among controls. Thalamic volumes among patients were also significantly correlated with bizarre behavior, hallucinations, and thought disorder. CONCLUSIONS: Findings suggest that connectivity between thalamic nuclei and prefrontal cortical areas are abnormal in chronic male schizophrenic patients. In addition, ventricular enlargement may be, in part, due to subtle reduction in thalamic volume and/or in volume of thalamocortical and corticothalamic fibers secondary to thalamic abnormalities. Finally, correlations with positive symptomatology underscore the role of the thalamus in gating or filtering of sensory information and coordination of cortical processing.

Increased rate of P300 latency prolongation with age in schizophrenia. Electrophysiological evidence for a neurodegenerative process.

BACKGROUND: The latency of the P300 event-related potential is prolonged in disorders associated with neural damage and degeneration and also becomes prolonged in the course of neural changes that accompany aging. We tested whether the rate of P300 latency increase with age was greater in male schizophrenic patients than in normal subjects because a steeper slope in schizophrenia would suggest a progressive neurodegenerative process. We also evaluated a subset of these subjects for changes in brain volumes as determined by magnetic resonance imaging. METHOD: The P300 component was elicited during an auditory "oddball" paradigm and was recorded from 47 male patients with chronic schizophrenia whose mean age at onset was 22.4 years and from 47 age-, handedness-, and gender-matched control subjects. The relation of P300 latency and amplitude to age within each group was evaluated using correlation and regression analyses. Brain volumes determined via magnetic resonance imaging were evaluated by quantitative volumetric analyses of images acquired with three-dimensional Fourier transform and double echo-spin echo-pulse sequences. RESULTS: The slope of P300 latency on age was steeper for schizophrenic patients than for normal control subjects at midline frontal and central electrode sites. The slope of N100 latency did not differ, implying that the P300 differences were not likely to be due to peripheral hearing loss or damage affecting the initial stages of neural processing. Posterior superior temporal gyrus gray matter volume determined via magnetic resonance imaging significantly diminished with age on the left side in patients with schizophrenia but not on the right side or in controls; these slopes were not, however, statistically significantly different from each other. CONCLUSIONS: These findings provide preliminary evidence that male patients with chronic schizophrenia experience a neurodegenerative process that becomes evident in adulthood and is reflected by the rate of change of P300 latency with age. Whether this process is due to the primary effects of schizophrenia or is secondary to factors associated with schizophrenia's chronic course and treatment remains a question for future investigation.

Auditory ERPs to non-target stimuli in schizophrenia: relationship to probability, task-demands, and target ERPs.

The effects of task demands and stimulus probability on the N1 and P2 components of the auditory event-related potential (ERP) to non-target stimuli were investigated in normal and medicated schizophrenic subjects. Subjects either read a book while tones were presented, or counted the rare (low probability) tones in an auditory oddball paradigm. The mismatch negativity to rare tones in the reading condition was present, and did not differ between groups. N1 amplitude was smaller in schizophrenic patients in all conditions. When subjects counted the rare tones, the amplitude and latency of P2 increased. This task-related effect on P2 was much greater in control than in schizophrenic subjects. Difference ERPs were used to better characterize the effect of task demands by subtracting the ERP in the reading condition from the ERP in the counting condition. The difference ERP consisted of a negative deflection at 182 ms, and a positive deflection at 276 ms, which were both reduced in schizophrenic subjects. N2 and P3 amplitude to target stimuli were reduced in patients as well, but these abnormalities were uncorrelated with N1 and P2 abnormalities to non-target stimuli. Despite automatic registration of stimulus mismatch, and normal processing speed, patients showed deficient task-related modulation of processing to both non-target and target stimuli. Reduction of N1 amplitude in schizophrenia occurs regardless of task demands, and may reflect a chronic, early-stage disturbance in information processing.

Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal.

Increased discharge activity of mesopontine cholinergic neurons participates in the production of electroencephalographic (EEG) arousal; such arousal diminishes as a function of the duration of prior wakefulness or of brain hyperthermia. Whole-cell and extracellular recordings in a brainstem slice show that mesopontine cholinergic neurons are under the tonic inhibitory control of endogenous adenosine, a neuromodulator released during brain metabolism. This inhibitory tone is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current. These data provide a coupling mechanism linking neuronal control of EEG arousal with the effects of prior wakefulness, brain hyperthermia, and the use of the adenosine receptor blockers caffeine and theophylline.

Parametric manipulations of auditory stimuli differentially affect P3 amplitude in schizophrenics and controls.

Schizophrenics show P3 amplitude reduction and topographic asymmetries. It is unclear whether the underlying cause of these deficits is primarily functional or structural. This study examined the effect of stimulus discriminability and task instruction on behavioral performance and P3 in schizophrenics and normal control subjects. Stimulus discriminability was manipulated by varying the overall loudness and pitch disparity of the two tones in an auditory oddball paradigm. Instructions emphasized either speed or accuracy of response. Instructions had no significant effects on reaction time, perceptual sensitivity, response bias, or P3. With increased discriminability, however, both groups improved in mean reaction time to targets and perceptual sensitivity. In controls, P3 became earlier and larger with increased stimulus discriminability and was consistently larger over left temporal areas than over right temporal areas. In schizophrenics, P3 latency was related to stimulus discriminability, but amplitude was not; P3 amplitude did not increase with improvement of perceptual sensitivity and reaction time. Unlike normal controls, schizophrenics had a P3 asymmetry at temporal sites, with reduced left-sided voltages. The results are not consistent with a primarily functional cause of P3 aberrations in schizophrenia and are compatible with the hypothesis that P3 amplitude deficits in schizophrenia are related to underlying pathophysiology of temporal lobe generator sites.

P300 topographic asymmetries are present in unmedicated schizophrenics.

Our laboratory has repeatedly found a left < right auditory P300 temporal lobe topographic asymmetry in right-handed, medicated schizophrenics. To determine whether this asymmetry was attributable to the effects of antipsychotic medications, we collected auditory "odd-ball" P300 event-related potentials from 14 right-handed, unmedicated schizophrenics (withdrawn from medication for an average of 21 days) and 14 right-handed, normal controls. Analysis of normalized P300 amplitudes showed a statistically significant difference in the voltage distributions between groups (a group by temporal electrode site interaction) that was consistent with a left < right temporal voltage asymmetry in schizophrenics but not in the normal controls. We conclude that P300 topographic asymmetries are present in unmedicated schizophrenics. These data are compatible with the growing body of data suggesting left temporal lobe structural abnormalities in schizophrenia.

Reversed temporal region asymmetries of P300 topography in left- and right-handed schizophrenic subjects.

The auditory P300 evoked potential was recorded in 36 subjects: left- (LH) and right-handed (RH) schizophrenic males and LH and RH normal controls. LH and RH normals showed no asymmetry in P300 scalp topography. LH and RH schizophrenics, however, showed lateralized asymmetries in temporal scalp regions: left < right P300 voltage asymmetry in RH schizophrenics and left > right P300 voltage asymmetry in LH schizophrenics. These data suggest that the schizophrenic pathology of P300 neural generators is lateralized according to handedness and provide the first evidence that LH and RH schizophrenics can be dissociated based on left-right voltage asymmetries in P300 topography. These findings further emphasize the need for control of handedness in P300 studies of schizophrenia.

The brain as a dream state generator: an activation-synthesis hypothesis of the dream process.

Recent research in the neurobiology of dreaming sleep provides new evidence for possible structural and functional substrates of formal aspects of the dream process. The data suggest that dreaming sleep is physiologically determined and shaped by a brain stem neuronal mechanism that can be modeled physiologically and mathematically. Formal features of the generator processes with strong implications for dream theory include periodicity and automaticity of forebrain activation, suggesting a preprogrammed neural basis for dream mentation in sleep; intense and sporadic activation of brain stem sensorimotor circuits including reticular, oculomotor, and vestibular neurons, possibly determining spatiotemporal aspects of dream imagery; and shifts in transmitter ratios, possibly accounting for dream amnesia. The authors suggest that the automatically activated forebrain synthesizes the dream by comparing information generated in specific brain stem circuits with information stored in memory.