Testing a Neuropsychological Model of Depersonalization with TMS

Depersonalization disorder (DPD) is a psychiatric condition affecting about 1% of the population. It comprises distressing and pervasive feelings of and emotional numbing unreality. Recent research using brain imaging and measures of bodily arousal (using skin conductance responses (SCR)) - a bit like the 'lie detector' - suggests abnormalities in the way such patients regulate and control their emotions. A part of the brain, the right ventro-lateral prefrontal cortex normally controls the 'emotional brain' including a region called the insula. We will test the hypothesis that DPD stems from abnormally increased prefrontal inhibition of the insula and predict that reducing frontal inhibition in patients with DPD should alleviate symptoms. Patients with DPD have reduced SCR which is linked to reduced activation in brain areas underpinning emotion affect, and by increased activation in prefrontal areas involved in emotion regulation. We can safely and temporarily dampen down this increased prefrontal activation using repeated magnetic pulses applied to the outside of the head for about 15 minutes, called repetitive transcranial magnetic stimulation (rTMS). This is commonly used as a research tool in neuroscience and when given over a period of days or weeks, a treatment for several psychotic conditions including depression. We can target the rTMS to the precise brain region we are interested in using standard magnetic resonance imaging (MRI) brain scans and a computer program linked to the TMS equipment. We will contrast the effects of low frequency (inhibitory) and high frequency (stimulatory) TMS and also a pretend or sham condition which feels like TMS but there is no magnetic field. We will study 3 groups of 20 healthy volunteers randomised to high, low or sham rTMS and 2 groups of 20 DPD patients, randomised to low-frequency or sham. We will measure participants' SCR and subjective arousal ratings when looking at a set of emotional photos. Symptoms of DPD will also be assessed. We predict that: 1. in DPD patients, low-frequency rTMS induced suppression of prefrontal activity will result in: increased SCR and enhanced subjective ratings of emotion to arousing pictures (plus reduced symptoms) versus pre-TMS levels. 2. in healthy volunteers, high-frequency rTMS stimulation will activate the same prefrontal regions leading to transient blunting of subjective and SCR responses resembling those of depersonalized participants, versus pre-TMS level. Low frequency (and sham) should have no effect. The study will contribute to knowledge of emotional regulation in health and disease and if positive, will pave the way for a therapeutic trial of rTMS in DPD.

Depersonalization disorder (DPD) comprises distressing and pervasive feelings of unreality and emotional numbing. Recent psychophysiological and neuroimaging research suggests dysfunction in the normal regulation of emotion - through reciprocal connections between right ventro-lateral prefrontal and limbic (including the insula) systems. We will test the hypothesis that DPD stems from increased prefrontal-insula inhibitory regulation and predict that reducing frontal inhibition in patients with DPD should alleviate symptoms. DPD is characterized by attenuated skin conductance responses (SCR), functionally related to reduced activation in brain areas underpinning affect, and by increased activation in prefrontal areas involved in emotion regulation. We will use MRI guided repetitive transcranial magnetic stimulation (rTMS) in contrasting, randomised, participant-blind interventions (low and high frequency stimulation and sham) in 3 groups of 20 healthy volunteers; and low frequency (versus sham) rTMS in 2 groups of 20 DPD patients; low-frequency TMS disrupts and high-frequency, enhances neural activity. We will measure two co-primary outcomes: objective SCR and subjective arousal ratings to emotional pictures. Symptoms of DPD will be a secondary outcome. We predict that: in DPD patients, low-frequency (1Hz) rTMS induced suppression of right ventro-lateral prefrontal activity will result in: increased SCR and enhanced subjective ratings of emotion to arousing pictures (plus reduced symptoms) versus pre-TMS levels; in healthy volunteers, high-frequency (10Hz) rTMS stimulation will activate the same prefrontal regions leading to transient blunting of subjective and autonomic responses resembling those of depersonalized participants, versus pre-TMS level. Low frequency will lead to increased emotion ratings, and sham no effects. The study will contribute to knowledge of emotional regulation and if positive, will pave the way for a therapeutic trial of rTMS in DPD.

Depersonalization disorder is a relatively common, extremely distressing and incapacitating condition, for which there are no approved or proven treatments. Its prevalence has been shown to be as high as that of schizophrenia or mood bipolar disorder - around 1% in the general population, although rates as a comorbid condition of depression or anxiety disorders range from 20-40%. Its onset is usually in teenage years or early adulthood and the condition is commonly persistent. There is however significant underrecognition and misdiagnosis. Research has found that it takes an average of 12 years for patients to receive an adequate diagnosis.
Findings from the study will contribute to the burgeoning field of 'affective neuroscience' and emotion regulation in health and disease. This includes how emotions can be suppressed or enhanced and how this affects judgement, well being and empathy.
The role of the ventro-lateral prefrontal cortex in this process is incompletely understood and this study will add to our knowledge. This could have clinical implications in terms of understanding the effects of damage and disease to this region.
Several psychiatric disorders can be viewed within the framework of emotional dysregulation, including dissociation, PTSD, personality and affective disorders. More specifically the research will enable us to refine our model of depersonalization, and how prefrontal areas contribute to a sense of self and emotional engagement. If patients undergoing low frequency transcranial magnetic stimulation experience the predicted reduction of depersonalization scores, then a formal double-blind randomised controlled treatment trial would be justified to explore clinical applications. This could begin as soon as the results from the current study are available.