Tom Holroyd

Neural dynamics for facial threat processing as revealed by gamma band synchronization using MEG

Facial threat conveys important information about imminent environmental danger. The rapid detection of this information is critical for survival and social interaction. However, due to technical and methodological difficulties, the spatiotemporal profile for facial threat processing is unknown. By utilizing magnetoencephalography (MEG), a brain-imaging technique with superb temporal resolution and fairly good spatial resolution, Synthetic Aperture Magnetometry (SAM), a recently developed source analysis technique, and a sliding window analysis, we identified the spatiotemporal development of facial threat processing in the gamma frequency band. We also tested the dual-route hypothesis by LeDoux who proposed, based on animal research, that there are two routes to the amygdala: a quick subcortical route and a slower and cortical route. Direct evidence with humans supporting this model has been lacking. Moreover, it has been unclear whether the subcortical route responds specifically to fearful expressions or to threatening expressions in general. We found early event-related synchronizations (ERS) in response to fearful faces in the hypothalamus/thalamus area (10-20 ms) and then the amygdala (20-30 ms). This was even earlier than the ERS response seen to fearful faces in visual cortex (40-50 ms). These data support LeDouxs suggestion of a quick, subcortical thamalo-amygdala route. Moreover, this route was specific for fear expressions; the ERS response in the amygdala to angry expressions had a late onset (150-160 ms). The ERS onset in prefrontal cortex followed that seen within the amygdala (around 160-210 ms). This is consistent with its role in higher-level emotional/cognitive processing.

Human Hippocampal and Parahippocampal Theta during Goal-Directed Spatial Navigation Predicts Performance on a Virtual Morris Water Maze

The hippocampus and parahippocampal cortices exhibit theta oscillations during spatial navigation in animals and humans, and in the former are thought to mediate spatial memory formation. Functional specificity of human hippocampal theta, however, is unclear. Neuromagnetic activity was recorded with a whole-head 275-channel magnetoencephalographic (MEG) system as healthy participants navigated to a hidden platform in a virtual reality Morris water maze. MEG data were analyzed for underlying oscillatory sources in the 4–8 Hz band using a spatial filtering technique (i.e., synthetic aperture magnetometry). Source analyses revealed greater theta activity in the left anterior hippocampus and parahippocampal cortices during goal-directed navigation relative to aimless movements in a sensorimotor control condition. Additional analyses showed that left anterior hippocampal activity was predominantly observed during the first one-half of training, pointing to a role for this region in early learning. Moreover, posterior hippocampal theta was highly correlated with navigation performance, with the former accounting for 76% of the variance of the latter. Our findings suggest human spatial learning is dependent on hippocampal and parahippocampal theta oscillations, extending to humans a significant body of research demonstrating such a pivotal role for hippocampal theta in animal navigation.

Anterior Cingulate Desynchronization and Functional Connectivity with the Amygdala During a Working Memory Task Predict Rapid Antidepressant Response to Ketamine

Pregenual anterior cingulate cortex (pgACC) hyperactivity differentiates treatment responders from non-responders to various pharmacological antidepressant interventions, including ketamine, an N-methyl-D-aspartate receptor antagonist. Evidence of pgACC hyperactivition during non-emotional working memory tasks in patients with major depressive disorder (MDD) highlights the importance of this region for processing both emotionally salient and cognitive stimuli. However, it is unclear whether pgACC activity might serve as a potential biomarker of antidepressant response during working memory tasks as well, in line with previous research with emotionally arousing tasks. This study tested the hypothesis that during the N-back task, a widely used working memory paradigm, low pretreatment pgACC activity, as well as coherence between the pgACC and the amygdala, would be correlated with the clinical improvement after ketamine. Magnetoencephalography (MEG) recordings were obtained from 15 drug-free patients with MDD during working memory performance 1 to 3 days before receiving a single ketamine infusion. Functional activation patterns were analyzed using advanced MEG source analysis. Source coherence analyses were conducted to quantify the degree of long-range functional connectivity between the pgACC and the amygdala. Patients who showed the least engagement of the pgACC in response to increased working memory load showed the greatest symptomatic improvement within 4 h of ketamine administration (r=0.82, p=0.0002, false discovery rate (FDR) <0.05). Pretreatment functional connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change (r=−0.73, p=0.0021, FDR <0.05).These data implicate the pgACC and its putative interaction with the amygdala in predicting antidepressant response to ketamine in a working memory task context.

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.

Emotional Automaticity Is a Matter of Timing

There has been a long controversy concerning whether the amygdalas response to emotional stimuli is automatic or dependent on attentional load. Using magnoencephalography and an advanced beamformer source localization technique, we found that amygdala automaticity was a function of time: while early amygdala responding to emotional stimuli (40–140 ms) was unaffected by attentional load, later amygdala response (280–410 ms), subsequent to frontoparietal cortex activity, was modulated by attentional load.

Hunting for neuronal currents: absence of rapid MRI signal changes during visual-evoked response

While recent reports have advocated the use of magnetic resonance imaging (MRI) to detect the effects of neuronal currents associated with human brain activity, only preliminary experimental data have been presented so far to demonstrate the feasibility of the method. Furthermore, it has not been adequately demonstrated that (1) MRI can separate neuronal current (NC) effects from other effects such as blood oxygen level-dependent (BOLD) contrast; (2) MRI has adequate sensitivity to detect NCs in vivo. In this work, we introduce a method that can separate slow (e.g., BOLD) processes from potential rapid (e.g., NC) processes and apply this method to investigate whether MRI allows detection of an NC response to a visual stimulus. MRI studies (n = 8) at 3.0 T using a sensitive multichannel detector showed insignificant effects related to NCs (averaged t < 0.05), in the presence of a highly significant BOLD signal (t = 6.15 +/- 0.90). In contrast, magnetoencephalography (MEG) experiments performed under similar conditions on the same subjects showed highly significant electrical activity (t = 7.90 +/- 2.28). It is concluded that, under the conditions used in this study, the sensitivity of MRI to detect evoked responses through NCs is at least an order of magnitude below that of BOLD-based functional MRI (fMRI) or MEG and too low to be practically useful.

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. Hum Brain Mapp, 2009.

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.

Neural responses to auditory stimulus deviance under threat of electric shock revealed by spatially-filtered magnetoencephalography

Stimulus novelty or deviance may be especially salient in anxiety-related states due to sensitization to environmental change, a key symptom of anxiety disorders such as posttraumatic stress disorder (PTSD). We aimed to identify human brain regions that show potentiated responses to stimulus deviance during anticipatory anxiety. Twenty participants (14 men) were presented a passive oddball auditory task in which they were exposed to uniform auditory stimulation of tones with occasional deviations in tone frequency, a procedure that elicits the mismatch negativity (MMN) and its magnetic counterpart (MMNm). These stimuli were presented during threat periods when participants anticipated unpleasant electric shocks, and safe periods when no shocks were anticipated. Neuromagnetic data were collected with a 275-channel whole-head MEG system and event-related beamformer analyses were conducted to estimate source power across the brain in response to stimulus deviance. Source analyses revealed greater right auditory and inferior parietal activity to stimulus deviance under threat relative to safe conditions, consistent with locations of MMN and MMNm sources identified in other studies. Structures related to evaluation of threat, left amygdala and right insula, also showed increased activity to stimulus deviance under threat. As anxiety level increased across participants, right and left auditory cortical as well as right amygdala activity increased to stimulus deviance. These findings fit with evidence of a potentiated MMN in PTSD relative to healthy controls, and warrant closer evaluation of how these structures might form a functional network mediating sensitization to stimulus deviance during anticipatory anxiety.

Abnormal Hippocampal Functioning and Impaired Spatial Navigation in Depressed Individuals: Evidence From Whole-Head Magnetoencephalography

OBJECTIVE Dysfunction of the hippocampus has long been suspected to be a key component of the pathophysiology of major depressive disorder. Despite evidence of hippocampal structural abnormalities in depressed patients, abnormal hippocampal functioning has not been demonstrated. The authors aimed to link spatial navigation deficits previously documented in depressed patients to abnormal hippocampal functioning using a virtual reality navigation task. METHOD Whole-head magnetoencephalography (MEG) recordings were collected while participants (19 patients diagnosed with major depressive disorder and 19 healthy subjects matched by gender and age) navigated a virtual Morris water maze to find a hidden platform; navigation to a visible platform served as a control condition. Behavioral measures were obtained to assess navigation performance. Theta oscillatory activity (4-8 Hz) was mapped across the brain on a voxel-wise basis using a spatial-filtering MEG source analysis technique. RESULTS Depressed patients performed worse than healthy subjects in navigating to the hidden platform. Robust group differences in theta activity were observed in right medial temporal cortices during navigation, with patients exhibiting less engagement of the anterior hippocampus and parahippocampal cortices relative to comparison subjects. Left posterior hippocampal theta activity was positively correlated with individual performance within each group. CONCLUSIONS Consistent with previous findings, depressed patients showed impaired spatial navigation. Dysfunction of right anterior hippocampus and parahippocampal cortices may underlie this deficit and stem from structural abnormalities commonly found in depressed patients.