Neuroimaging studies of depression have demonstrated treatment-specific changes involving the limbic system and regulatory regions in the prefrontal cortex. While these studies have examined the effect of short-term, interpersonal or cognitive-behavioural psychotherapy, the effect of long-term, psychodynamic intervention has never been assessed. Here, we investigated recurrently depressed (DSM-IV) unmedicated outpatients (N = 16) and control participants matched for sex, age, and education (N = 17) before and after 15 months of psychodynamic psychotherapy. Participants were scanned at two time points, during which presentations of attachment-related scenes with neutral descriptions alternated with descriptions containing personal core sentences previously extracted from an attachment interview. Outcome measure was the interaction of the signal difference between personal and neutral presentations with group and time, and its association with symptom improvement during therapy. Signal associated with processing personalized attachment material varied in patients from baseline to endpoint, but not in healthy controls. Patients showed a higher activation in the left anterior hippocampus/amygdala, subgenual cingulate, and medial prefrontal cortex before treatment and a reduction in these areas after 15 months. This reduction was associated with improvement in depressiveness specifically, and in the medial prefrontal cortex with symptom improvement more generally. This is the first study documenting neurobiological changes in circuits implicated in emotional reactivity and control after long-term psychodynamic psychotherapy.

Introduction

Neuroimaging approaches have been used to investigate neurobiological changes in depressive patients in studies that address remission after psychotherapy or antidepressant medication [1]–[2]. The majority of these studies focused on the effect of treatment on brain metabolism or perfusion at rest. A more recent series of functional neuroimaging (fMRI) studies has turned to the use of experimental tasks to examine processes that may be more directly involved in emotional appraisal and control processes [3]–[6]. To date, studies examining the functional neuroanatomy of psychotherapy in depressed patients have applied interpersonal therapy or cognitive behavioural therapy [7]–[8]. The present research reports on the first fMRI study with recurrently depressed patients treated with psychodynamic psychotherapy. Long-term psychodynamic psychotherapy has been shown to be associated with larger improvement in these difficult forms of depression than shorter treatments [9]–[10].

The interest aroused by neuroimaging studies of treatment of depression is in part due to their potential importance in shedding light on the mechanism of therapy. There is considerable evidence for increased activation in limbic areas in depression, especially the amygdala, under exposure to emotional stimuli [5]–[8], [11]–[12]. This limbic activation may be related to an increased reactivity of depressed patients to emotional stimuli of negative valence [13]. It has been proposed that antidepressant medication acts directly on this abnormal reactivity [1], since amygdalar activation normalizes in medicated remission [5]–[6]. However, changes associated with depression have also been reported for prefrontal regions during the execution of cognitive tasks [14]. Because of the regulatory nature of many processes mapped onto the prefrontal cortex, these changes may refer to mechanisms involved in emotional regulation during the acute depressive episode, or reflect deficits in cognitive control [15]–[16]. Different interpretations of signal changes in the prefrontal cortex in depression or after therapy may be given [17]. Given that emotion regulation may either have adverse or protective roles in mental health, depending on the mechanism through which it operates [18]–[19], it may be important to determine not only if, but also how emotions are regulated [20].

Psychodynamic approaches propose that depression, besides its biological and social underpinnings, may be meaningfully conceived as a specific organization of an individual's conscious or unconscious beliefs and feelings. The resulting mental operations constitute defensive strategies that aim at avoiding negative feelings arising out of conflict in order to maximize a subjective sense of safety [21]. The objective of long-term psychodynamic psychotherapy is a stable modification of these strategies that allows the patient to work through, achieve insight, and reappraise experiences that are related to depressive pathology. Therefore, in our study we would expect neural patterns of appraisal of sensitive material to change during therapy and move from emotion regulation styles characterized by unfavourable strategies to more integrated acceptance and awareness. The identification of these neural patterns was the general aim of our study.

To date, only one fMRI study has investigated the effect of psychotherapy (cognitive behavioural therapy) on major depression using a standardized experimental task (Fu et al., [22]). In this study, participants were exposed to faces portraying different degrees of sadness. This study detected changes in the amygdala-anterior hippocampus and posterior cingulate-precuneus regions as well as the superior frontal gyrus, suggesting that areas associated in previous studies with increased reactivity to emotional stimuli and mechanisms of control are also relevant for psychotherapy effects.

In the present study, patients with recurrent unipolar depression underwent functional neuroimaging scans at the beginning of treatment and after 15 months, during which they were treated with psychodynamic psychotherapy by experienced therapists. A matched healthy control group without psychotherapy was scanned at the same time points. The stimulus materials were attachment-related pictures from the Adult Attachment Projective Picture System (AAP [23]), a measure that has been shown to be valid for use in an fMRI environment [24]–[25]. These pictures are designed to elicit mental engagement with attachment-related experiences such as separation, illness, danger, and loss. The fundamental ability to form attachment is indispensable for human social relationships. Since Bowlby's seminal contributions [26], attachment and separation have become essential theoretical components of developmental psychology, and psychodynamic theory [27]. One key feature of interpersonal problems in depressed patients is their feelings of helplessness and fear of losing the love of a significant other [28]. Internal representations of the self as unlovable and of attachment figures as unloving are a central dimension of Beck's cognitive triad of depression [29].

To increase the capacity of the signal to elicit a response related to the emotional processes of each individual, material was here prepared using personalized content [11], [30]–[32] derived from AAP interviews with each participant. In the personally relevant condition the AAP attachment scenes were accompanied by individually tailored descriptions containing core sentences from the patient's own narrative previously elicited by each picture (see Material and methods for details). The same series of attachment scenes accompanied by a standard factual, non-emotional description for all participants was used as control condition.

In addition to the detection of a neural signature of treatment, we were interested to see the extent in which the pattern of change corresponded or differed from the one described by Fu et al. [22]. On the basis of this study, we formulated specific hypotheses relative to the general aim of the study of characterizing changes in neural patterns of appraisal and emotion regulation occurring after therapy. Our first hypothesis was the normalization of emotional reactivity indexed by changes in the amygdala-anterior hippocampus region, as found by Fu et al. [22]. Our second hypothesis was the existence of changes in prefrontal areas detected in previous studies [22], [31], [33] as possible markers of the specific effect of psychodynamic psychotherapy on styles of emotion regulation [1], [8].

The present design differed from that of previous studies in several further respects. As mentioned before, neuroimaging studies have examined the effects of short time psychotherapy (e.g. 12–20 weeks), applying cognitive-behavioural or interpersonal therapy [7]–[8]. We examined depressed patients with a history of several previous depressive episodes during psychodynamic treatment providing a longer observation window (15 months of therapy) than in previous studies.

The present investigation therefore complements the existing emerging picture of changes associated with the therapy of depression emerging from neuroimaging studies. In meta-analyses of neuroimaging studies of the effect of psychopharmacological intervention [34], decreased activation following treatment was reported in the anterior hippocampus and parahippocampal cortex, in the subgenual and pregenual cingulus, in the insula, and the putamen. In the prefrontal cortex, decreased activation was reported in the middle and superior left frontal gyrus. The frontal lobes, however, were also the seat of several meta-analytic foci of increased activation following treatment (in the middle frontal gyri bilaterally and the dorsal anterior cingulate cortex). Further increased activation was found in the posterior cingulate cortex and in temporo-parietal regions on both sides. With the exception of Fu et al. [22], neuroimaging studies of psychotherapy of depression have examined only resting state metabolism (for reviews, see [7]–[8], [35]). Here, therapy outcomes were associated primarily with changes in the prefrontal cortex (dorsolateral, ventrolateral, and medial) [36]–[38], but the direction of changes was not entirely consistent. Some studies reported reduced rest metabolism or perfusion that normalized at endpoint [37]–[38]. In other studies, however, this finding was reversed [36]. When both psychotherapy and pharmacotherapy were compared [37], there was limited overlap between changes found in these two therapy modalities. While all these studies appear to be broadly compatible with the involvement of limbic and prefrontal areas, more studies of task-related activation are needed to provide a comprehensive picture of changes associated with remission.