Sequence Variation Associated with SLC12A5 Gene Expression Is Linked to Brain Structure and Function in Healthy Adults.

A single-nucleotide polymorphism in the promoter region of the Matrix Metalloproteinase-9 (MMP9) gene, rs3918242, has been shown to affect MMP9 expression in macrophages and was associated with schizophrenia by two independent groups. However, rs3918242's effects on MMP9 expression were not replicable in cell lines or brain tissue. Additionally, publically available data indicate that rs3918242 genotype is related not to MMP9 expression, but rather to expression of SLC12A5, a nearby gene coding for a K+/Cl- cotransporter, whose expression has also been related to schizophrenia. Here, we studied brain structure and function in healthy participants stratified by rs3918242 genotype using structural MRI (N = 298), functional MRI during an N-back working memory task (N = 554), and magnetoencephalography (MEG) during the same task (N = 190). We found rs3918242 was associated with gray matter volume (GMV) in the insula and dorsolateral prefrontal cortex bilaterally, closely replicated in discovery and replication samples; and with inferior parietal lobule (IPL) GMV when the samples were meta-analytically combined. Additionally, using both fMRI and MEG, rs3918242 was associated with right IPL working memory-related activation, replicated in two cohorts and across imaging modalities. These convergent results provide further impetus for examinations of the relationship of SLC12A5 with brain structure and function in neuropsychiatric disease.

Prefrontal high gamma during a magnetoencephalographic working memory task.

In human electrophysiology research, the high gamma part of the power spectrum (~>60 Hz) is a relatively new area of investigation. Despite a low signal-to-noise ratio, evidence exists that it contains significant information about activity in local cortical networks. Here, using magnetoencephalography (MEG), we found high gamma activity when comparing data from an n-back working memory task to resting data in a large sample of normal volunteers. Initial analysis of power spectra from 0-back, 2-back, and rest trials showed three frequency bands exhibiting task-related differences: alpha, beta, and high gamma. Unlike alpha and beta, the high gamma spectrum was broad, without a peak at a single frequency. In addition, power in high gamma was highest for the 2-back and lowest during rest, while the opposite pattern occurred in the other bands. Beamformer source localization of each of the three frequency bands revealed a distinct set of sources for high gamma. These included several regions of prefrontal cortex that exhibited greater power when both n-back conditions were compared to rest. A subset of these regions had more power when the 2-back was compared to 0-back, which indicates a role in working memory performance. Our results show that high gamma will be important for understanding cortical processing during cognitive and other tasks. Furthermore, data from human intracortical recordings suggest that high gamma is the aggregate of spiking in local cortical networks, which implies that MEG could serve to bridge experimental modalities by noninvasively observing task-related modulation of spiking rates.

Deriving frequency-dependent spatial patterns in MEG-derived resting state sensorimotor network: A novel multiband ICA technique.

Recently, independent components analysis (ICA) of resting state magnetoencephalography (MEG) recordings has revealed resting state networks (RSNs) that exhibit fluctuations of band-limited power envelopes. Most of the work in this area has concentrated on networks derived from the power envelope of beta bandpass-filtered data. Although research has demonstrated that most networks show maximal correlation in the beta band, little is known about how spatial patterns of correlations may differ across frequencies. This study analyzed MEG data from 18 healthy subjects to determine if the spatial patterns of RSNs differed between delta, theta, alpha, beta, gamma, and high gamma frequency bands. To validate our method, we focused on the sensorimotor network, which is well-characterized and robust in both MEG and functional magnetic resonance imaging (fMRI) resting state data. Synthetic aperture magnetometry (SAM) was used to project signals into anatomical source space separately in each band before a group temporal ICA was performed over all subjects and bands. This method preserved the inherent correlation structure of the data and reflected connectivity derived from single-band ICA, but also allowed identification of spatial spectral modes that are consistent across subjects. The implications of these results on our understanding of sensorimotor function are discussed, as are the potential applications of this technique. Hum Brain Mapp 38:779-791, 2017. © 2016 Wiley Periodicals, Inc.

Convergent BOLD and Beta-Band Activity in Superior Temporal Sulcus and Frontolimbic Circuitry Underpins Human Emotion Cognition.

The processing of social information in the human brain is widely distributed neuroanatomically and finely orchestrated over time. However, a detailed account of the spatiotemporal organization of these key neural underpinnings of human social cognition remains to be elucidated. Here, we applied functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in the same participants to investigate spatial and temporal neural patterns evoked by viewing videos of facial muscle configurations. We show that observing the emergence of expressions elicits sustained blood oxygenation level-dependent responses in the superior temporal sulcus (STS), a region implicated in processing meaningful biological motion. We also found corresponding event-related changes in sustained MEG beta-band (14-30 Hz) oscillatory activity in the STS, consistent with the possible role of beta-band activity in visual perception. Dynamically evolving fearful and happy expressions elicited early (0-400 ms) transient beta-band activity in sensorimotor cortex that persisted beyond 400 ms, at which time it became accompanied by a frontolimbic spread (400-1000 ms). In addition, individual differences in sustained STS beta-band activity correlated with speed of emotion recognition, substantiating the behavioral relevance of these signals. This STS beta-band activity showed valence-specific coupling with the time courses of facial movements as they emerged into full-blown fearful and happy expressions (negative and positive coupling, respectively). These data offer new insights into the perceptual relevance and orchestrated function of the STS and interconnected pathways in social-emotion cognition.

Group differences in MEG-ICA derived resting state networks: Application to major depressive disorder.

UNLABELLED: Functional magnetic resonance imaging (fMRI) studies have revealed the existence of robust, interconnected brain networks exhibiting correlated low frequency fluctuations during rest, which can be derived by examining inherent spatio-temporal patterns in functional scans independent of any a priori model. In order to explore the electrophysiological underpinnings of these networks, analogous techniques have recently been applied to magnetoencephalography (MEG) data, revealing similar networks that exhibit correlated low frequency fluctuations in the power envelope of beta band (14-30Hz) power. However, studies to date using this technique have concentrated on healthy subjects, and no method has yet been presented for group comparisons. We extended the ICA resting state MEG method to enable group comparisons, and demonstrate the technique in a sample of subjects with major depressive disorder (MDD). We found that the intrinsic resting state networks evident in fMRI appeared to be disrupted in individuals with MDD compared to healthy participants, particularly in the subgenual cingulate, although the electrophysiological correlates of this are unknown. Networks extracted from a combined group of healthy and MDD participants were examined for differences between groups. Individuals with MDD showed reduced correlations between the subgenual anterior cingulate (sgACC) and hippocampus in a network with primary nodes in the precentral and middle frontal gyri. Individuals with MDD also showed increased correlations between insulo-temporal nodes and amygdala compared to healthy controls. To further support our methods and findings, we present test/re-test reliability on independent recordings acquired within the same session. Our results demonstrate that group analyses are possible with the resting state MEG-independent component analysis (ICA) technique, highlighting a new pathway for analysis and discovery. This study also provides the first evidence of altered sgACC connectivity with a motor network. This finding, reliable across multiple sessions, suggests that the sgACC may partially mediate the psychomotor symptoms of MDD via synchronized changes in beta-band power, and expands the idea of the sgACC as a hub region mediating cognitive and emotional symptomatic domains in MDD. Findings of increased connectivity between the amygdala and cortical nodes further support the role of amygdalar networks in mediated depressive symptomatology. CLINICAL TRIALS IDENTIFIER: NCT00024635 (ZIA-MH002927-04).

Cross-frequency power coupling between hierarchically organized face-selective areas.

Neural oscillations are linked to perception and behavior and may reflect mechanisms for long-range communication between brain areas. We developed a causal model of oscillatory dynamics in the face perception network using magnetoencephalographic data from 51 normal volunteers. This model predicted induced responses to faces by estimating oscillatory power coupling between source locations corresponding to bilateral occipital and fusiform face areas (OFA and FFA) and the right superior temporal sulcus (STS). These sources showed increased alpha and theta and decreased beta power as well as selective responses to fearful facial expressions. We then used Bayesian model comparison to compare hypothetical models, which were motivated by previous connectivity data and a well-known theory of temporal lobe function. We confirmed this theory in detail by showing that the OFA bifurcated into 2 independent, hierarchical, feedforward pathways, with fearful expressions modulating power coupling only in the more dorsal (STS) pathway. The power coupling parameters showed a common pattern over connections. Low-frequency bands showed same-frequency power coupling, which, in the dorsal pathway, was modulated by fearful faces. Also, theta power showed a cross-frequency suppression of beta power. This combination of linear and nonlinear mechanisms could reflect computational mechanisms in hierarchical feedforward networks.

Neuronal avalanches in the resting MEG of the human brain.

What constitutes normal cortical dynamics in healthy human subjects is a major question in systems neuroscience. Numerous in vitro and in vivo animal studies have shown that ongoing or resting cortical dynamics are characterized by cascades of activity across many spatial scales, termed neuronal avalanches. In experiment and theory, avalanche dynamics are identified by two measures: (1) a power law in the size distribution of activity cascades with an exponent of -3/2 and (2) a branching parameter of the critical value of 1, reflecting balanced propagation of activity at the border of premature termination and potential blowup. Here we analyzed resting-state brain activity recorded using noninvasive magnetoencephalography (MEG) from 124 healthy human subjects and two different MEG facilities using different sensor technologies. We identified large deflections at single MEG sensors and combined them into spatiotemporal cascades on the sensor array using multiple timescales. Cascade size distributions obeyed power laws. For the timescale at which the branching parameter was close to 1, the power law exponent was -3/2. This relationship was robust to scaling and coarse graining of the sensor array. It was absent in phase-shuffled controls with the same power spectrum or empty scanner data. Our results demonstrate that normal cortical activity in healthy human subjects at rest organizes as neuronal avalanches and is well described by a critical branching process. Theory and experiment have shown that such critical, scale-free dynamics optimize information processing. Therefore, our findings imply that the human brain attains an optimal dynamical regime for information processing.

Spatiotemporal Alterations in Working Memory-Related Beta Band Neuromagnetic Activity of Patients With Schizophrenia On and Off Antipsychotic Medication: Investigation With MEG.

BACKGROUND AND HYPOTHESIS: We used the uniquely high combined spatial and temporal resolution of magnetoencephalography to characterize working memory (WM)-related modulation of beta band activity in neuroleptic-free patients with schizophrenia in comparison to a large sample of performance-matched healthy controls. We also tested for effects of antipsychotic medication on identified differences in these same patients. STUDY DESIGN: Inpatients with schizophrenia (n = 21) or psychotic disorder not otherwise specified (n = 4) completed N-back and control tasks during magnetoencephalography while on placebo and during antipsychotic medication treatment, in a blinded, randomized, counterbalanced manner. Healthy, performance-matched controls (N = 100) completed the same tasks. WM-related neural activation was estimated as beta band (14-30 Hz) desynchronization throughout the brain in successive 400 ms time windows. Voxel-wise statistical comparisons were performed between controls and patients while off-medication at each time window. Significant clusters resulting from this between-groups analysis were then used as regions-of-interest, the activations of which were compared between on- and off-medication conditions in patients. STUDY RESULTS: Controls showed beta-band desynchronization (activation) of a fronto-parietal network immediately preceding correct button press responses-the time associated with WM updating and task execution. Altered activation in medication-free patients occurred largely during this time, in prefrontal, parietal, and visual cortices. Medication altered patients' neural responses such that the activation time courses in these regions-of-interest more closely resembled those of controls. CONCLUSIONS: These findings demonstrate that WM-related beta band alterations in schizophrenia are time-specific and associated with neural systems targeted by antipsychotic medications. Future studies may investigate this association by examining its potential neurochemical basis.

Cognitive fitness of cost-efficient brain functional networks.

The human brain's capacity for cognitive function is thought to depend on coordinated activity in sparsely connected, complex networks organized over many scales of space and time. Recent work has demonstrated that human brain networks constructed from neuroimaging data have economical small-world properties that confer high efficiency of information processing at relatively low connection cost. However, it has been unclear how the architecture of complex brain networks functioning at different frequencies can be related to behavioral performance on cognitive tasks. Here, we show that impaired accuracy of working memory could be related to suboptimal cost efficiency of brain functional networks operating in the classical beta frequency band, 15-30 Hz. We analyzed brain functional networks derived from magnetoencephalography data recorded during working-memory task performance in 29 healthy volunteers and 28 people with schizophrenia. Networks functioning at higher frequencies had greater global cost efficiency than low-frequency networks in both groups. Superior task performance was positively correlated with global cost efficiency of the beta-band network and specifically with cost efficiency of nodes in left lateral parietal and frontal areas. These results are consistent with biophysical models highlighting the importance of beta-band oscillations for long-distance functional connections in brain networks and with pathophysiological models of schizophrenia as a dysconnection syndrome. More generally, they echo the saying that "less is more": The information processing performance of a network can be enhanced by a sparse or low-cost configuration with disproportionately high efficiency.

Ingestion-controlling network: what's language got to do with it?

The prevalence of obesity has increased dramatically worldwide, whereas the types of treatment and their efficacy have not substantially changed over the last two decades. Additionally, drugs used to control weight gain could occasionally create untoward effects in cardiovascular functions, as well as in behaviors, memory, sleep, and emotions because the molecular machinery responsible for ingestion control is interconnected with or shared by the above domains. How each group of drugs preserves the privacy of its message in the mutual network is not fully understood. In the present essay, the graph theory approach was used to explore some aspects of molecular signaling as though they were a 'language'. Its emphasis is on 'molecular polysemy', a term that refers to the ability of biomolecules to be used like words in natural languages more than one-way. This has physiological and clinical implications, in particular when planning drug designs with "specially engineered shotgun loads" that target a combination of biomolecules that assure a better therapeutic outcome without causing deficits in connected but patho-physiologically irrelevant bystanders.

A preliminary study of the neural mechanisms of frustration in pediatric bipolar disorder using magnetoencephalography.

BACKGROUND: Irritability is prevalent and impairing in pediatric bipolar disorder (BD) but has been minimally studied using neuroimaging techniques. We used magnetoencephalography (MEG) to study theta band oscillations in the anterior cingulate cortex (ACC) during frustration in BD youth. ACC theta power is associated with attention to emotional stimuli, and the ACC may mediate responses to frustrating stimuli. METHODS: We used the affective Posner task, an attention paradigm that uses rigged feedback to induce frustration, to compare 20 medicated BD youth (14.9+/-2.0 years; 45% male) and 20 healthy controls (14.7+/-1.7 years; 45% male). MEG measured neuronal activity after negative and positive feedback; we also compared groups on reaction time, response accuracy, and self-reported affect. Patients met strict DSM-IV BD criteria and were euthymic. Controls had no psychiatric history. RESULTS: BD youth reported more negative affective responses than controls. After negative feedback, BD subjects, relative to controls, displayed greater theta power in the right ACC and bilateral parietal lobe. After positive feedback, BD subjects displayed lower theta power in the left ACC than did controls. Correlations between MEG, behavior, and affect were nonsignificant. CONCLUSION: In this first MEG study of BD youth, BD youth displayed patterns of theta oscillations in the ACC and parietal lobe in response to frustration-inducing negative feedback that differed from healthy controls. These data suggest that BD youth may display heightened processing of negative feedback and exaggerated self-monitoring after frustrating emotional stimuli. Future studies are needed with unmedicated bipolar youth, and comparison ADHD and anxiety groups.

Visual awareness, emotion, and gamma band synchronization.

What makes us become aware? A popular hypothesis is that if cortical neurons fire in synchrony at a certain frequency band (gamma), we become aware of what they are representing. We tested this hypothesis adopting brain-imaging techniques with good spatiotemporal resolution and frequency-specific information. Specifically, we examined the degree to which increases in event-related synchronization (ERS) in the gamma band were associated with awareness of a stimulus (its detectability) and/or the emotional content of the stimulus. We observed increases in gamma band ERS within prefrontal-anterior cingulate, visual, parietal, posterior cingulate, and superior temporal cortices to stimuli available to conscious awareness. However, we also observed increases in gamma band ERS within the amygdala, visual, prefrontal, parietal, and posterior cingulate cortices to emotional relative to neutral stimuli, irrespective of their availability to conscious access. This suggests that increased gamma band ERS is related to, but not sufficient for, consciousness.

Magnetoencephalographic gamma power reduction in patients with schizophrenia during resting condition.

OBJECTIVE: The "default network" represents a baseline condition of brain function and is of interest in schizophrenia research because its component brain regions are believed to be aberrant in the disorder. We hypothesized that magnetoencephalographic (MEG) source localization analysis would reveal abnormal resting activity within particular frequency bands in schizophrenia. EXPERIMENTAL DESIGN: Eyes-closed resting state MEG signals were collected for two comparison groups. Patients with schizophrenia (N = 38) were age-gender matched with healthy control subjects (N = 38), and with a group of unmedicated unaffected siblings of patients with schizophrenia (N = 38). To localize 3D-brain regional differences, synthetic aperture magnetometry was calculated across established frequency bands as follows: delta (0.9-4 Hz), theta (4-8 Hz), alpha (8-14 Hz), beta (14-30 Hz), gamma (30-80 Hz), and super-gamma (80-150 Hz). PRINCIPLE OBSERVATIONS: Patients with schizophrenia showed significantly reduced activation in the gamma frequency band in the posterior region of the medial parietal cortex. As a group, unaffected siblings of schizophrenia patients also showed significantly reduced activation in the gamma bandwidth across similar brain regions. Moreover, using the significant region for the patients and examining the gamma band power gave an odds ratio of 6:1 for reductions of two standard deviations from the mean. This suggests that the measure might be the basis of an intermediate phenotype. CONCLUSIONS: MEG resting state analysis adds to the evidence that schizophrenic patients experience this condition very differently than healthy controls. Whether this baseline difference relates to network abnormalities remains to be seen.

Top-down beta oscillatory signaling conveys behavioral context in early visual cortex.

Top-down modulation of sensory processing is a critical neural mechanism subserving numerous important cognitive roles, one of which may be to inform lower-order sensory systems of the current 'task at hand' by conveying behavioral context to these systems. Accumulating evidence indicates that top-down cortical influences are carried by directed interareal synchronization of oscillatory neuronal populations, with recent results pointing to beta-frequency oscillations as particularly important for top-down processing. However, it remains to be determined if top-down beta-frequency oscillations indeed convey behavioral context. We measured spectral Granger Causality (sGC) using local field potentials recorded from microelectrodes chronically implanted in visual areas V1/V2, V4, and TEO of two rhesus macaque monkeys, and applied multivariate pattern analysis to the spatial patterns of top-down sGC. We decoded behavioral context by discriminating patterns of top-down (V4/TEO-to-V1/V2) beta-peak sGC for two different task rules governing correct responses to identical visual stimuli. The results indicate that top-down directed influences are carried to visual cortex by beta oscillations, and differentiate task demands even before visual stimulus processing. They suggest that top-down beta-frequency oscillatory processes coordinate processing of sensory information by conveying global knowledge states to early levels of the sensory cortical hierarchy independently of bottom-up stimulus-driven processing.

Amygdala activation in affective priming: a magnetoencephalogram study.

We employed magnetoencephalography (MEG) to examine amygdala activity during a linguistic affective priming task. The experimental design included positive and negative word pairs. Using synthetic aperture magnetometry in the analysis of MEG data, we identified a left amygdala power increase in the theta frequency range during priming involving negative words. We found that the amygdala displayed a time-dependent intensification in responsiveness to negative stimuli, specifically between 150 and 400 ms after target presentation. This study provides evidence for theta power changes in the amygdala and demonstrates that the analysis of brain oscillations provides a powerful tool to explore mechanisms implicated in emotional processing.

Threat of shock increases excitability and connectivity of the intraparietal sulcus.

Anxiety disorders affect approximately 1 in 5 (18%) Americans within a given 1 year period, placing a substantial burden on the national health care system. Therefore, there is a critical need to understand the neural mechanisms mediating anxiety symptoms. We used unbiased, multimodal, data-driven, whole-brain measures of neural activity (magnetoencephalography) and connectivity (fMRI) to identify the regions of the brain that contribute most prominently to sustained anxiety. We report that a single brain region, the intraparietal sulcus (IPS), shows both elevated neural activity and global brain connectivity during threat. The IPS plays a key role in attention orienting and may contribute to the hypervigilance that is a common symptom of pathological anxiety. Hyperactivation of this region during elevated state anxiety may account for the paradoxical facilitation of performance on tasks that require an external focus of attention, and impairment of performance on tasks that require an internal focus of attention.

Prefrontal electrophysiologic "noise" and catechol-O-methyltransferase genotype in schizophrenia.

BACKGROUND: Increased variability of stimulus-induced prefrontal electromagnetic activity ("noise") has been associated with genetic risk for schizophrenia. On the basis of animal experiments and computational models, we have predicted that this prefrontal "noise" phenotype would be related to variation in prefrontal dopamine (DA) signaling, which itself might be abnormal in schizophrenia. In the present study, the effect of a functional single nucleotide polymorphism (val(108/158)met) within the catechol-O-methyltransferase (COMT) gene on prefrontal "noise" was examined, because the COMT enzyme is involved in cortical synaptic dopamine metabolism and weakly predictive of risk for schizophrenia. METHODS: A Caucasian sample comprising 112 unrelated normal subjects, 83 schizophrenic probands, and 87 of their unaffected siblings was investigated, all of whom had measures of prefrontal "noise" estimated from event-related electroencephalogram during an auditory oddball task. RESULTS: The val(108/158)met genotype was significantly associated with prefrontal "noise"; homozygous Val-carriers had greatest prefrontal "noise" values; odds ratio (OR) = 2.37 (95% confidence interval [CI] 1.37-4.10), p = 003. The genotype-phenotype association was stronger when only considering male subjects with an OR = 3.37 (95% CI: 1.63-6.98), p = 002. CONCLUSIONS: The results suggest that COMT genotype impacts the level of prefrontal physiologic "noise."

Instability of prefrontal signal processing in schizophrenia.

OBJECTIVE: Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phase-synchronization (i.e., an increased stimulus-related variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. METHOD: Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. RESULTS: In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a "fractionized" and unfocussed pattern of activation in patients. CONCLUSIONS: These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia.

The G72/G30 gene complex and cognitive abnormalities in schizophrenia.

A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p=0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p=0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.

Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment.

The purpose of this pilot study was to: (1) determine if regional brain volume change occurs in schizophrenia patients during very short periods of withdrawal from, or stable treatment with, antipsychotics, and; (2) compare results of region-of-interest (ROI) to voxel-based morphometry (VBM) methods. In two small groups of schizophrenic inpatients, magnetic resonance imaging was performed before and after antipsychotic withdrawal, and at two time points during stable chronic antipsychotic treatment. Regional brain volumes were measured using ROI methods. Grey matter volume was measured with VBM. The medication withdrawal group showed no effect of treatment state or antipsychotic type on regional brain volumes with ROI analysis, but effects of both treatment state and antipsychotic type on grey matter volume were observed with VBM in right middle frontal, right medial frontal, right and left superior frontal, right cingulate, and right superior temporal gyrii as well as in the right and left hippocampal gyrii. The chronic stable treatment group showed an effect of time on right caudate, left hippocampal, and total cerebrospinal fluid volumes with ROI analysis, while effects of both time and antipsychotic type were observed with VBM on grey matter volume in the left superior temporal lobe. No findings survived correction for multiple comparisons. A positive correlation between regional volume change and emerging psychopathology was demonstrated using ROI methods in the medication withdrawal group. Treatment state and emergent symptoms in schizophrenia patients were associated with regional volume change over very short time periods. Longitudinal regional brain volume change in schizophrenia patients is likely physiologic and therefore potentially reversible.