Auditory evoked magnetic fields in adults with fragile X syndrome.

Hyper-reactivity and anxiety to sensory stimuli have been described in patients with fragile X syndrome (FXS), and may be related to abnormal processing in afferent sensory pathways. We used magnetoencephalography (MEG) to measure auditory responses to pure tones in 11 adults with FXS and 11 non-FXS subjects. The amplitude for the N100m auditory evoked field component was significantly higher for patients with FXS than for subjects. FXS subjects also had less lateralized N100m anterior-posterior dipole locations. These data may suggest that more neurons are activated by acoustic stimuli in FXS, consistent with subjective experience of increased stimulus intensity. Anomalous cerebral lateralization may suggest an early critical window for effects on neocortical development of the fragile X mental retardation protein (FMRP) produced by the FMR1 gene in individuals with FXS.

Reduced hippocampal volume in association with p50 nonsuppression following traumatic brain injury.

Traumatic brain injury (TBI) may produce persistently impaired auditory gating. This cholinergic-dependent, hippocampally mediated preattentive cognitive function that facilitates filtering of auditory stimuli may be indexed by the P50 evoked waveform to paired auditory stimuli. Abnormal P50 suppression post TBI is believed to result from injury to the hippocampus and/or its afferent cholinergic projections. This hypothesis was tested by comparing hippocampal and total brain volumes on MRI between ten P50-nonsuppressing TBI patients and ten normal control subjects matched for age, gender, and education. TBI subjects had highly significant bilateral hippocampal volume reductions, even when covaried for reductions in total brain volume. Degree of volume loss was not correlated with initial TBI severity. Findings support the hypothesis that hippocampal injury underlies P50 nonsuppression post TBI and suggest that such structural abnormalities may be observed even in "mildly" injured persons.

Fine structure of the auditory M100 in schizophrenia and schizoaffective disorder.

BACKGROUND: Several studies have demonstrated anomalous asymmetry of the 100-msec latency auditory-evoked field (M100) in schizophrenia. Recent evidence suggests this may be a compound component, however. Our study examines the localization of two M100 subcomponents in patients with schizophrenia and schizoaffective disorder. METHODS: Magnetoencephalographic recordings of auditory-evoked fields were obtained for 14 subjects with schizophrenia, 12 with schizoaffective disorder, and 23 control subjects. Two M100 subcomponents were identified and localized in each hemisphere. RESULTS: Both patient groups exhibited different lateralization compared with control subjects, with the second subcomponent tending to be less lateralized. CONCLUSIONS: The second subcomponent may be the major contributor to previously reported laterality differences. Future studies might benefit by separating M100 subcomponents so that specific functions could be addressed.

Neuromagnetic alpha suppression during an auditory sternberg task. Evidence for a serial, self-terminating search of short-term memory.

Reaction times (RT) during the Sternberg memory paradigm generally increase with memory set size, but do not differ for positive and negative probe stimuli. Sternberg proposed that this indicated that short-term memory (STM) scanning is both exhaustive and serial. However, this notion has received much criticism, primarily because RT must also reflect response selection factors. Magnetoencephalographic (MEG) recordings of auditory alpha-suppression have previously demonstrated that suppression duration is correlated with set size, potentially providing a physiological index of memory scanning time related specifically to sensory cortices. The current study expands earlier research into this metric by separately analyzing positive and negative probes. Thirteen normal adults participated in an auditory Sternberg paradigm. Pure tones were presented in memory set/probe combinations where the probe had a 50 percent chance of being within the memory set, and RT and accuracy were measured. Magnetic alpha-band activity (8-12 Hz) was quantified for pre- and post-stimulus regions. Although RT did not differ for positive and negative probes, alpha-suppression duration was greater for negative probes than positive ones, potentially indicating that scanning time was slightly faster in the positive condition. This may indicate that STM scanning is serial, but self-terminates when matching occurs.

Impaired auditory gating and P50 nonsuppression following traumatic brain injury.

Traumatic brain injury (TBI) can produce persistent attention and memory impairment that may in part be produced by impaired auditory sensory gating. The P50 evoked waveform response to paired auditory stimuli appears to be a useful measure of auditory gating. The first controlled measurement of the P50 ratio in TBI patients is described: when 20 patients with persistently symptomatic TBI were compared with 20 control subjects, the P50 ratio was significantly greater in the TBI group. The potential neurophysiologic and therapeutic implications of this finding in TBI patients who report symptoms consistent with impaired auditory gating are discussed.

Sex differences in the refractory period of the 100 ms auditory evoked magnetic field.

The 100 ms latency auditory evoked magnetic response (M100) has been implicated in the earliest stage of acoustic memory encoding in the brain. Sex differences in this response have been found in its location within the brain and its functional properties. We recorded the M100 in 25 adults in response to changes in interstimulus interval of an auditory stimulus. Response amplitudes of the M100 were used to compute a measure of the M100 refractory period, which has been proposed to index the decay time constant of echoic memory. This time constant was significantly longer in both hemispheres of the female participants when compared to the male participants. Possible implications of this for behavioral sex differences in human memory performance are discussed.

Hippocampal to pituitary volume ratio: a specific measure of reciprocal neuroendocrine alterations in alcohol dependence.

OBJECTIVE: Studies to date provide conflicting views of the relationship between corticosteroids and decreased hippocampal volume in alcoholism. If this were mediated through the hypothalamic-pituitary-adrenal (HPA) axis, enlarged pituitary volumes relative to hippocampal volumes might be expected and be measurable using the hippocampus to pituitary volume (H:P) ratio. METHOD: Using magnetic resonance imaging (MRI), we performed volumetric analysis of the pituitary and hippocampus on 10 subjects with alcohol dependence (AD) and on 10 normal control subjects. RESULTS: Compared to normal controls, AD subjects demonstrated a trend towards decreased hippocampal volume (p < .06) and increased pituitary volume (p < .07). More importantly, H:P ratios were significantly smaller in AD subjects (p < .01). This observation persisted even when covaried for age. CONCLUSIONS: Reduced H:P ratio fits the hypothesis that ethanol stimulates pituitary corticotrophs resulting in elevated corticosteroid levels and possible injury to the hippocampus. If replicated, reduced H:P ratio may serve as a clinical measure of reciprocal neuroendocrine changes in chronic heavy ethanol use.

Bipolar disorder: anomalous brain asymmetry associated with psychosis.

OBJECTIVE: Anomalous cerebral asymmetry in schizophreniform disorders has been described, but its presence in psychotic mood disorders has not been established. Measures of cerebral asymmetry may distinguish patients with psychotic mood disorders from those with nonpsychotic mood disorders and from comparison subjects. To test this hypothesis, the authors examined functional cerebral asymmetry by using a metric based on magnetic source imaging. METHOD: A total of 33 subjects participated. Nine were patients with bipolar I disorder and a negative history of psychotic symptoms during mood disorder episodes, 12 were patients with bipolar I disorder and a positive history of psychotic symptoms during mood disorder episodes, and 12 were nonpsychiatric comparison subjects. Equivalent current dipole generators in both hemispheres were estimated for the 20-msec-latency somatosensory evoked field (M20) component produced by stimulation of the contralateral median nerve. RESULTS: The comparison subjects demonstrated asymmetry in anterior-posterior equivalent current dipole locations of the M20 (right anterior to left), and the bipolar subjects with no history of psychosis were similarly asymmetric. The bipolar subjects with a history of psychosis during mood episodes, however, demonstrated a reversal of cerebral asymmetry of the M20 (left anterior to right). CONCLUSIONS: Cerebral lateralization of the M20 distinguished bipolar subjects with psychosis from those without psychosis and comparison subjects. The M20 is generated in area 3b of the postcentral gyrus. These findings suggest anatomical displacement of the postcentral gyrus in psychotic disorders and support the hypothesis that anomalous cerebral asymmetry is a feature of psychotic disorders generally, including psychotic mood disorders.

Schizoaffective disorder: evidence for reversed cerebral asymmetry.

BACKGROUND: Schizoaffective disorder is one of the most severe of the affective psychoses, but its pathophysiology is poorly understood. Because cerebral lateralization may be disturbed in psychotic disorders generally, studies examining cerebral asymmetry may improve understanding of the neurobiology specific to schizoaffective disorder. This study examines cerebral lateralization in this patient population using magnetic source localization. METHODS: We studied 16 subjects with schizoaffective disorder and 16 controls. Magnetic source localization was used to identify the location of the 20 msec latency somatosensory evoked field component (M20). RESULTS: In control subjects, the source location was further anterior in the right hemisphere. The subjects with schizoaffective disorder were reverse lateralized. CONCLUSIONS: The findings of a reversed asymmetry of the M20 in patients with schizoaffective disorder suggest an anatomical shift in the placement of the post central gyrus in this disorder, compatible with a disorder of cerebral lateralization. Whether this finding converges or diverges with measurement of the M20 in other psychotic disorders will require further investigation.

The thalamus and the schizophrenia phenotype: failure to replicate reduced volume.

BACKGROUND: Thalamic abnormalities resulting in impaired attention and information processing may form a foundation for cognitive and perceptual disturbances in schizophrenia. Measurements of the thalamus in patients with schizophrenia have shown reductions relative to normal comparison subjects. METHODS: In the current project, magnetic resonance images of the brain were obtained in 10 male and 11 female subjects with paranoid-type schizophrenia, and 15 male and 12 female normal comparison subjects. Total brain and bilateral thalamic volumes were calculated. RESULTS: There were no significant diagnosis, hemisphere, or gender differences in thalamic volumes. CONCLUSIONS: Structural thalamic abnormalities are not likely to universally and parsimoniously explain the schizophrenia phenotype. Abnormal thalamic size in patients with schizophrenia should be understood as reflecting one of several possible structural abnormalities contributing to production of the schizophrenia phenotype, but must be regarded with caution unless paired with functional studies.

Magnetoencephalography: applications in psychiatry.

Magnetoencephalography (MEG) measures the extracranial magnetic fields produced by intraneuronal ionic current flow within appropriately oriented cortical pyramidal cells. Based upon superconducting quantum interference device technology operating at liquid helium temperatures (4 K), MEG offers excellent temporal and spatial resolution for selected sources, and complements information obtained from electroencephalograms and other functional imaging strategies. Current instrumentation permits recording up to several hundred channels simultaneously with head-shaped dewars, although the cost of such systems is high. The fact that magnetic fields fall off with the square of the distance from the source is both a benefit (when separating activity in the two hemispheres) and a limitation (when attempting to record deep sources). The lack of skin contact facilitates using MEG to record direct current and very high frequency (> 600 Hz) brain activity. The clinical utility of MEG includes presurgical mapping of sensory cortical areas and localization of epileptiform abnormalities, and localization of areas of brain hypoperfusion in stroke patients. MEG studies in psychiatric disorders have contributed materially to improved understanding of anomalous brain lateralization in the psychoses, have suggested that P50 abnormalities may reflect altered gamma band activity, and have provided evidence of hemisphere-specific abnormalities of short-term auditory memory function.

EEG correlates of methylphenidate response among children with ADHD: a preliminary report.

BACKGROUND: Recent electrophysiologic studies have found fairly consistent differences between children with attention-deficit/hyperactivity disorder (ADHD) and age-matched control subjects. The present study examined electroencephalogram (EEG) changes associated with a double blind, placebo-controlled administration of methylphenidate among children with ADHD. METHODS: Subjects were 10 children, ages 8 to 13, with a primary diagnosis of ADHD. Brain electrical activity was recorded with 7 electrodes in the frontal, central, and midline areas during baseline and cognitive activation conditions. RESULTS: Repeated-measures ANOVAs indicate that children exhibiting a positive medication response had reductions of theta and alpha as well as increased beta in the frontal regions, while nonresponders showed the opposite pattern (p < .05). Significant correlations between improvement on a vigilance task and changes in beta activity in the frontal electrodes emerged as well. CONCLUSIONS: These preliminary findings indicate that there are different electrophysiologic correlates to methylphenidate among ADHD children who are medication responders and nonresponders.

Attention and memory dysfunction after traumatic brain injury: cholinergic mechanisms, sensory gating, and a hypothesis for further investigation.

Traumatic brain injury (TBI) is a common occurrence, with a rate of nearly 400,000 new injuries per year. Cognitive and emotional disturbances may become persistent and disabling for many injured persons, and frequently involve symptomatic impairment in attention and memory. Impairments in attention and memory have been well characterized in TBI, and are likely related to disruption of cholinergic functioning in the hippocampus. Additionally, disturbances in this neurotransmitter system may also account for disturbances in sensory gating and discriminative attention in this population. The electroencephalographic P50 waveform of the evoked response to paired auditory stimuli may provide a physiologic market of impaired sensory gating among TBI survivors. The first application of this recording assessment to the TBI population is reported. Preliminary findings in three cases are presented, and the interpretation of impaired sensory gating in this population is discussed. Given the impact of TBI on cholinergic systems, the effects of cholinergic augmentation on attention and memory impairment, and the availability of an electrophysiologic marker of cholinergic dysfunction responsive to cholinergic agents, a testable cholinergic hypothesis for investigation and treatment of these patients is proposed.

Magnetoencephalography and magnetic source imaging: technology overview and applications in psychiatric neuroimaging.

Magnetoencephalography (MEG) is an electrophysiologic brain imaging technology that has been applied to the study of mental illness, particularly schizophrenia. Like electroencephalography, it provides excellent temporal resolution, and in combination with magnetic resonance imaging, can also provide good spatial resolution. Studies of the auditory system in schizophrenia using MEG have demonstrated an abnormality in functional cerebral asymmetry, in which persons with schizophrenia typically show reduced, or reversed, cerebral asymmetry compared with normal subjects. This abnormality is sex-specific; it is more pronounced in males with schizophrenia. These findings have not been demonstrated using other neuroimaging strategies. Thus, MEG appears to offer a unique and valuable contribution to psychiatric neuroimaging. Current research and clinical applications of MEG are limited, however, by the high cost of instrumentation. The cost of MEG systems should improve as more applications are developed, in schizophrenia as well as other neuropsychiatric conditions, and hospitals begin to invest in the technology.

Sleep disorders presenting as psychiatric disorders.

In summary, disordered sleep can present in a complex and atypical fashion in which the primary sleep-related component may not be immediately apparent. A high index of suspicion serves the clinician well in these cases. A careful and systematic evaluation of sleep often proves to be rewarding in terms of diagnostic accuracy and improved treatment outcome.

Sequential source of the M100 exhibits inter-hemispheric asymmetry.

The most prominent auditory evoked field component occurs at about 100 ms latency and is termed the M100. We recorded M100 data from 20 subjects, in both hemispheres. We modeled the generators with a single equivalent current dipole in a 10 ms sliding window from 0 to 245 ms post-stimulus. A residual error curve was plotted, and a search for local minima identified two latencies at about 75 and 100 ms. In the left hemisphere, the early generator was about 6 mm above the later source; in the right hemisphere the early source was about 3 mm above the later, and 11 mm posterior. The M100 is a compound source, and the model may provide additional information in cases with reported laterality differences.

Developmental changes in refractoriness of the neuromagnetic M100 in children.

Considerable evidence exists for developmental changes in latency and amplitude of the auditory evoked potential termed N100. However, it is widely recognized that the N100 wave comprises multiple, temporally overlapping neural generators, and few data are available addressing either individual generator development or mechanisms behind such change. Using magnetoencelphalographic (MEG) measurements of the magnetic analog of the N100 termed the M100, which derives primarily from supra-temporal auditory generators, it is demonstrated here that changes in the response of that waveform to manipulation of interstimulus interval (ISI) occur between the ages of 6 and 18 years of age.

Elevated cytotoxicity in combat veterans with long-term post-traumatic stress disorder: preliminary observations.

Resting immune [WBC and differential cell counts lymphocyte phenotyping (CD2, CD4, CD8, CD16, CD20, and CD56), and NK activity] and endocrine (cortisol, prolactin, growth hormone, and DHEA-SO4) parameters were measured in 10 male, Vietnam combat veterans diagnosed with long-term post-traumatic stress disorder (PTSD) and 9 control Vietnam combat veterans without a PTSD diagnosis but with a comparable history of alcohol abuse. Subjects completed a battery of psychological questionnaires. We report on preliminary observations of the relationship between PTSD and physiological and psychological parameters. With some important exceptions, PTSD patients did not differ from the age-matched control group with regard to hormone levels or lymphocyte phenotypes. However, NK activity was higher in the PTSD population than in the controls. Beck, Mississippi, and Combat Exposure scores were significantly elevated in the PTSD population. In contrast to previous observations in depressed populations, depression (indicated by elevated Beck scores), comorbid with PTSD, was associated with increased natural cytotoxicity.

Sex-specific expression of Heschl's gyrus functional and structural abnormalities in paranoid schizophrenia.

OBJECTIVE: Evidence supports abnormal temporal lobe structure and function in schizophrenia. Some abnormalities, particularly involving the auditory cortex, appear to be sex specific. These findings were extended to anatomical and physiological descriptors. METHOD: The authors quantified the volume, surface area, and three-dimensional location of Heschl's gyri on magnetic resonance imaging (MRI) images of 21 patients with paranoid schizophrenia and 24 healthy comparison subjects. Neuromagnetic localizations of the 100-msec latency auditory evoked field (M100) were compared with MRI-determined locations of Heschl's gyri, computed as the geometric center of mass of the volume. RESULTS: Volumetric measures revealed small Heschl's gyri only in male patients. Asymmetry was found in the location of the Heschl's gyrus centroid (more anterior on the right) across all groups. Male comparison subjects had M100 locations posterior to the Heschl's gyrus centroid in the left hemisphere and close to the Heschl's gyrus centroid on the right, while male patients had M100 sources anterior to the Heschl's gyrus centroid on the left. All women had M100 locations posterior to the Heschl's gyrus centroid on the left and anterior to it on the right. CONCLUSIONS: These results demonstrate that some temporal lobe abnormalities in schizophrenia are sex specific. They also suggest that the anomalous lateralization of the auditory evoked field cannot be explained by a shift in the underlying anatomy, since the anatomical substrate is lateralized in both comparison subjects and patients of both sexes. These findings may indicate a sex-specific functional reorganization in the auditory cortex in schizophrenia.

Magnetic source imaging evidence of sex differences in cerebral lateralization in schizophrenia.

BACKGROUND: It has been postulated that schizophrenia represents a disorder of anomalous cerebral lateralization. This study is a replication of earlier preliminary findings using a multichannel neuromagnetometer, suggesting altered lateralization in schizophrenia in male subjects, with an extension of the findings to female subjects. METHODS: We used magnetoencephalography-based magnetic source imaging to estimate the intracranial location of the 100-millisecond latency auditory-evoked field component (M100) in both left and right hemispheres of 20 patients with paranoid schizophrenia and 20 controls without schizophrenia. Neuroanatomical data were obtained by means of magnetic resonance imaging, from which we segmented and computed volumes of both total brain and left and right superior temporal gyri. RESULTS: Locations of M100 source were compatible with neuronal generators located in the transverse gyri of Heschl on the superior temporal gyri in both study groups; M100 sources were asymmetric in all the control subjects. The male patient subgroup exhibited significantly less asymmetry than the control group, while the female patient subgroup actually showed significantly more asymmetry. The male patient subgroup generally had smaller superior temporal gyri than the control group. No evidence of total brain volume differences was observed. CONCLUSIONS: Our findings support previous magnetoencephalography-based studies suggesting anomalous cerebral lateralization in schizophrenia. Further, in extending our studies to female patients, our data suggest that the nature of this anomaly is sex specific, a finding that, to our knowledge, has not previously been reported.