Early effects of exposure-based cognitive behaviour therapy on the neural correlates of anxiety.

Exposure-based cognitive-behaviour therapy (CBT) for anxiety disorders is an effective intervention, but the brain mechanisms driving recovery are largely unknown. In this experimental medicine study, we investigated to what degree CBT affects neural markers of anxiety at an early stage of treatment, to identify dynamic mechanistic changes which might be crucial in the process of recovery as opposed to those seen following full treatment completion. In a randomised controlled trial, unmedicated patients with panic disorder either received four weekly sessions of exposure-based CBT (N = 14) or were allocated to a waiting group (N = 14). Symptom severity was measured before and after the intervention. During functional magnetic resonance imaging (fMRI), patients performed an emotion regulation task, either viewing negative images naturally, or intentionally down-regulating negative affect using previously taught strategies. Four-session CBT led to marked reductions in symptoms and 71% of patients reached recovery status (versus 7% in the control group). This intervention normalised brain hyperactivation previously seen in panic disorder, particularly in areas linked to threat monitoring, fear memory, and maladaptive emotion regulation, such as amygdala, dorsomedial and dorsolateral prefrontal cortex, and temporal gyrus. Our findings suggest that optimal treatment doses for panic disorder might be much lower than previously thought. Furthermore, this is the first study to show that neural markers of anxiety change very early during CBT, highlighting potential neural mechanisms that might drive clinical recovery. Such knowledge is important for the development of more compact combination treatments targeting these mechanisms more effectively. (Neural Effects of Cognitive-behaviour Therapy in Panic Disorder; clinicaltrials.gov; NCT03251235).

Predicting rapid response to cognitive-behavioural treatment for panic disorder: the role of hippocampus, insula, and dorsolateral prefrontal cortex.

Although cognitive-behavioural therapy (CBT) is an effective first-line intervention for anxiety disorders, treatments remain long and cost-intensive, difficult to access, and a subgroup of patients fails to show any benefits at all. This study aimed to identify functional and structural brain markers that predict a rapid response to CBT. Such knowledge will be important to establish the mechanisms underlying successful treatment and to develop more effective, shorter interventions. Fourteen unmedicated patients with panic disorder underwent 3 T functional and structural magnetic resonance imaging (MRI) before receiving four sessions of exposure-based CBT. Symptom severity was measured before and after treatment. During functional MRI, patients performed an emotion regulation task, either viewing negative images naturally, or intentionally down-regulating negative affect by using previously taught strategies of cognitive reappraisal. Structural MRI images were analysed including left and right segmentation and volume estimation. Improved response to brief CBT was predicted by increased pre-treatment activation in bilateral insula and left dorsolateral prefrontal cortex (dlPFC) during threat processing, as well as increased right hippocampal gray matter volume. Previous work links these regions to improved threat processing and fear memory activation, suggesting that the activation of such mechanisms is crucial for exposure-based CBT to be effective.

Vestibular inputs to human motion-sensitive visual cortex.

Two crucial sources of information available to an organism when moving through an environment are visual and vestibular stimuli. Macaque cortical area MSTd processes visual motion, including cues to self-motion arising from optic flow and also receives information about self-motion from the vestibular system. In humans, whether human MST (hMST) receives vestibular afferents is unknown. We have combined 2 techniques, galvanic vestibular stimulation and functional MRI (fMRI), to show that hMST is strongly activated by vestibular stimulation in darkness, whereas adjacent area MT is unaffected. The activity cannot be explained in terms of somatosensory stimulation at the electrode site. Vestibular input appears to be confined to the anterior portion of hMST, suggesting that hMST as conventionally defined may contain 2 subregions. Vestibular activity was also seen in another area previously implicated in processing visual cues to self-motion, namely the cingulate sulcus visual area (CSv), but not in visual area V6. The results suggest that cross-modal convergence of cues to self-motion occurs in both hMST and CSv.

Spatial attention changes excitability of human visual cortex to direct stimulation.

Conscious perception depends not only on sensory input, but also on attention [1, 2]. Recent studies in monkeys [3-6] and humans [7-12] suggest that influences of spatial attention on visual awareness may reflect top-down influences on excitability of visual cortex. Here we tested this specifically, by providing direct input into human visual cortex via cortical transcranial magnetic stimulation (TMS) to produce illusory visual percepts, called phosphenes. We found that a lower TMS intensity was needed to elicit a conscious phosphene when its apparent spatial location was attended, rather than unattended. Our results indicate that spatial attention can enhance visual-cortex excitability, and visual awareness, even when sensory signals from the eye via the thalamic pathway are bypassed.

Chronostasis without voluntary action.

In a previous study we explored auditory chronostasis and suggested an arousal account of this temporal illusion rather than one dependent on backdating actions to the onset of a motor event. Here we present three experiments designed to distinguish between two competing accounts of the mechanisms underlying the illusion. Experiment 1 investigated whether voluntary movements are necessary for the illusion to occur. Experiment 2 sought to clarify whether auditory chronostasis occurs when the intervals to be judged are continuous (temporally contiguous) rather than separate events. Experiment 3 was designed to establish whether increased task demands account for the illusion. Together the results from these experiments show that chronostasis is an illusion that is not dependent on voluntary action, can occur without a change in the spatial location of the stimulus (thus precluding an account based on spatial attention), occurs with discrete as well as continuous events, and is affected by the salience of the termination of the event to be timed rather than the onset. Collectively these findings suggest that the mechanisms underlying chronostasis are best explained by an arousal hypothesis since neither attention nor backdating to action can account for the commonalities between chronostasis in the auditory, visual and tactile domains.

Phosphene threshold as a function of contrast of external visual stimuli.

Transcranial magnetic stimulation (TMS) of the occipital lobe is frequently used to induce visual percepts by direct stimulation of visual cortex. The threshold magnetic field strength necessary to elicit a visual percept is often regarded as a measure of electrical excitability of visual cortex. Using single-pulse TMS during visual motion stimulus presentation, we investigated the relationship between different degrees of visual cortical preactivation and cortical phosphene threshold (PT). The two possible, mutually exclusive, predictions on the outcome of this experiment were that a) PT increases with stronger preactivation because of a decrease in the signal-to-noise ratio, or b) that PT decreases with increased preactivation because of the increase in neuronal response towards some threshold. PTs for single-pulse stimulation of the occipital lobe were determined for eight subjects while they passively viewed a horizontally drifting luminance-modulated sinewave grating. Gratings used were of four different luminance contrasts while the spatial and temporal frequencies remained constant. PTs were shown to increase significantly as the background grating increased in contrast. These results suggest that the neural activity underlying the perception of a phosphene can be considered a type of signal that can be partially masked by another signal, in this case the visual cortical activation produced by passive viewing of drifting gratings.

The site of saccadic suppression.

During rapid eye movements, or saccades, stable vision is maintained by active reduction of visual sensitivity. The site of this saccadic suppression remains uncertain. Here we show that phosphenes--small illusory visual perceptions--induced by transcranial magnetic stimulation (TMS) to the human occipital cortex are immune to saccadic suppression, whereas phosphenes induced by retinal stimulation are not, thus providing direct physiological evidence that saccadic suppression occurs between the retina and the occipital visual cortex.

Perception of self-motion from peripheral optokinetic stimulation suppresses visual evoked responses to central stimuli.

In a previous functional neuroimaging study we found that early visual areas deactivated when a rotating optical flow stimulus elicited the illusion of self-motion (vection) compared with when it was perceived as a moving object. Here, we investigated whether electrical cortical responses to an independent central visual probe stimulus change as a function of whether optical flow stimulation in the periphery induces the illusion of self-motion or not. Visual-evoked potentials (VEPs) were obtained in response to pattern-reversals in the central visual field in the presence of a constant peripheral large-field optokinetic stimulus that rotated around the naso-occipital axis and induced intermittent sensations of vection. As control, VEPs were also recorded during a stationary peripheral stimulus and showed no difference than those obtained during optokinetic stimulation. The VEPs during constant peripheral stimulation were then divided into two groups according to the time spans where the subjects reported object- or self-motion, respectively. The N70 VEP component showed a significant amplitude reduction when, due to the peripheral stimulus, subjects experienced self-motion compared to when the peripheral stimulus was perceived as object-motion. This finding supplements and corroborates our recent evidence from functional neuroimaging that early visual cortex deactivates when a visual flow stimulus elicits the illusion of self-motion compared with when the same sensory input is interpreted as object-motion. This dampened responsiveness might reflect a redistribution of sensorial and attentional resources when the monitoring of self-motion relies on a sustained and veridical processing of optic flow and may be compromised by other sources of visual input.

Posture and mental task performance when viewing a moving visual field.

We investigated the characteristics of standing posture and performance of concurrent cognitive tasks in subjects confronted by whole field visual motion. Movements of the head and centre of pressure (COP) were recorded in 12 subjects who performed modified Brooks spatial and verbal tasks when in quiet stance viewing a chequerboard pattern, planar, visual field, moving with uniform velocity (25 degrees /s, 50 degrees /s and 76 degrees /s). Eight subjects were also tested seated to control for the effect of stance. Task load was monitored by heart rate and eye movements were recorded to ensure viewing compliance. Subjects rated their quotidian susceptibility to visual disorientation on a validated scale. In both lateral and antero-posterior directions there were small amplitude but significant increases in COP sway path length and standard deviations of both COP and head sway during exposure to visual motion in proportion to visual flow speed. Performing cognitive tasks during visual motion attenuated sway S.D. The effects on sway of task and visual flow were independent. Visual motion induced a slight tilt and turn of the head and body in the direction of flow together with slight neck flexion. Errors on both verbal and spatial tasks increased >250% during visual motion both when standing and when seated. Ratings of subjects' susceptibility to disorientation were un-related to either verbal or spatial task error rates. A current hypothesis is that the enhancement of sway by visual motion is destabilisation. We propose an alternative explanation that sway enhancement could be exploratory 'testing of the ground' movements to check for self motion. Hence decrease in sway magnitude during a cognitive task could be caused by a reduction in exploratory movement because attention is diverted from postural control to a secondary task. Mere passive viewing of a moving visual field may interfere with cognitive tasks possibly because the threat of disorientation by whole field motion diverts attentional resources.

Auditory chronostasis: hanging on the telephone.

The perception of time can be illusory: we have all waited anxiously for important seconds to tick away slowly at the end of a football game and have experienced the truth of the adage "time flies when you're having fun." One illusion of time experience that has recently been investigated, the apparent slowing of the movement of the second hand on the clock when one first looks at it, has been termed "chronostasis," and it has been suggested that the effect is unique to vision and is dependent on eye movements. We sought to test whether the effect is really unique to vision or whether it can also be produced with auditory stimuli. Subjects were asked to judge the length of a silent gap between two tones presented through headphones. When the tones were presented to one ear, subjects judged the duration of the gap veridically. When subjects were required to shift concentration from one ear to the other, however, the judgement of time showed that the auditory system is also susceptible to chronostasis. We suggest that this generalization of chronostasis to another sensory system is consistent with theories of time perception that emphasize a single, multimodal clock for duration estimation rather than a mechanism that is dependent on motor acts.

Neural correlates of visual-motion perception as object- or self-motion.

Both self-motion and objects moving in our visual field generate visual motion by displacing images on the retina. Resolving this ambiguity may seem effortless but large-field visual-motion stimuli can yield perceptual rivalry between the real percept of object-motion and the illusory percept of self-motion (vection). We used functional magnetic resonance imaging to record brain activity in human observers exposed to constant-velocity roll-motion. This stimulus induced responses in areas reaching from calcarine to parieto-occipital and to ventral and lateral temporo-occipital cortex and the anterior insula. During vection, early motion-sensitive visual areas and vestibular parieto-insular cortex deactivated, whereas higher-order parieto- and temporo-occipital areas known to respond to optical flow retained identical activity levels. Within this sustained response, these latter areas displayed transient activations in response to each perceptual switch as identified in event-related analyses. Our results thus show that these areas are responsive to the type of visual motion stimulus and highly sensitive to its perceptual bistability. The only region to be more active during perceived self-motion was in, or close to, the cerebellar nodulus. This activation may correspond to the gain increase of torsional optokinetic nystagmus during vection and/or to changes in sensory processing related to the rotational percept. In conclusion, we identified neural correlates of perceiving self-motion from vision alone, i.e., in the absence of confirmatory vestibular or proprioceptive input. These functional properties preserve the organism's ability to move accurately in its environment by relying on visual cues under conditions when the other spatial senses fail to provide such information.

Percept-related changes in horizontal optokinetic nystagmus at different body orientations in space.

Large-field motion of the visual environment is a powerful stimulus to induce the perception of contra-directional self-motion in a stationary observer. We investigated the interrelations between horizontal optokinetic nystagmus and subjective states of motion perception under variation of subjects' orientation with respect to gravity. Subjects were tested sitting upright and lying supine, and signalled transitions between object- and self-motion perception whilst viewing an optokinetic stimulus rotating about the subjects' longitudinal axis at a range of angular velocities. Optokinetic stimulation in the supine condition resulted in subjects perceiving a graviceptive conflict and the illusory perception of whole body tilt in a direction opposite to optokinetic stimulus rotation, whereas during upright viewing the axis of stimulus rotation was aligned with the direction of gravity and thus did not result in a conflict or perception of tilt. In both postures, self-motion perception coincided with an increased deviation of mean horizontal gaze position in the perceived direction of heading with a concurrent reduction in optokinetic nystagmus slow-phase gain. Slow-phase gain was also significantly reduced in the supine position as well as at increasing stimulus velocities. The results demonstrate that spontaneous transitions between the perception of object-motion and that of self-motion consistently coincide with spatial attentional and orientational strategies, shifting from passive monitoring to active oculomotor exploration and anticipation.

Visual motion stimulation, but not visually induced perception of self-motion, biases the perceived direction of verticality.

Large-field torsional optokinetic stimulation is known to affect the perceived direction of gravity with verticality judgements deviating towards the direction of visual stimulus rotation. The present study aimed to replicate this effect and to examine it further by subjecting participants to optokinetic stimulation in roll, resulting in spontaneous alternations between the perception of object-motion and that of contradirectional self-motion (vection), as reported by the subjects. Simultaneously, subjects were oscillated laterally in a flight simulator and indicated their perception of postural verticality. Results confirmed that rotation of the visual environment in the frontal plane biases the perceived orientation of gravity towards the direction of visual stimulus motion. However, no differential effect of perceptual state on postural verticality was obtained when contrasting verticality judgements made during the perception of object-motion with those obtained during reported self-motion perception. This finding is likely to reflect a functional segregation of central nervous visual-vestibular subsystems that process the perception of self-tilt and that of self-rotation to some degree independently.

Vision: when the clock appears to stop.

Eye movements produce a temporary loss of visual sensitivity known as saccadic suppression, and a distortion of space perception known as saccadic compression. A new study has reported a seemingly related phenomenon --chronostasis---in which one's perception of time also undergoes an illusory distortion during rapid movements of the eyes.