To our knowledge, this is the first reported case demonstrating that both treatment-resistant major depression and its response to ketamine can occur in the absence of the basolateral amygdala. Influential reports regarding the neurobiological origin of depression have highlighted a central role for the amygdala in the pathogenesis of depression (10–12). While there are heterogeneous findings of amygdala activity in major depression, possibly as a result of differences in contrast selection (13, 14), recent meta-analytic evidence indicates that major depression is associated with blunted amygdala responses to negative stimuli (13). Likewise, a meta-analysis found reduced amygdala volume in unmedicated patients (15), but there are also reports of amygdala enlargement in acutely depressed patients (16). Notably, pretreatment amygdala hyporeactivity has been identified as a general predictor of treatment response (17), and neurofeedback-based increases in amygdala hemodynamic activity can mitigate depressive symptoms (18). Furthermore, major depression has also been associated with dysfunctions in large-scale brain networks (19, 20). One of the most consistent findings is hyperconnectivity of the default mode network (DMN), which encompasses the posterior and anterior cortical midline structures and shows increased activation during self-referential processing in the resting state (21). It has been suggested that the DMN assigns valence to internally represented stimuli, and the DMN has been linked to self-focused rumination in major depression (22). By contrast, patients with major depression have been found to exhibit hypoconnectivity within the frontoparietal network (FPN) and salience network (SAN). The FPN plays a pivotal role in cognitive control of emotional responses (23) and the SAN, comprising the dorsal anterior cingulate cortex, fronto-insular cortex, and amygdala, is crucially involved in determining the biological significance of external stimuli (24). Interestingly, multiple depressive episodes may lead to a temporal decoupling of the amygdala from SAN regions (25).
Although we are not aware of any past reports of treatment-resistant major depression following bilateral amygdala damage, there have been reports of depressive symptoms in amygdala-lesioned patients, such as in the original case study of patient S.M. (32), where it was noted that “she has occasionally reported depressive symptomatology, related to difficult situational exigencies.” A more recent report (33) confirmed this observation and noted that one of the most difficult situations for patient S.M. is her social isolation, leading to feelings of loneliness and abandonment. Similarly, A.M. only developed major depression after a series of adverse life events, all happening in quick succession, and all involving the loss of close family members and feelings of loneliness and abandonment. If A.M.’s twin sister were to experience a similar fate, it remains possible that she would also be at risk for developing major depression. Clearly, a bilateral amygdala lesion is not sufficient for the development of major depression, but it may render individuals more vulnerable to the effects of social isolation, which appears to be a common consequence of having amygdala damage in free-ranging rhesus monkeys (34).
A.M.’s depression featured pronounced and uncontrollable negative cognitive biases and ruminations, and it is possible that an intact amygdala normally helps to inhibit such dysfunctional thought processes, although this is still speculative and needs to be explored further. It has been hypothesized that the amygdala updates the valuation of “self” representations in the orbital frontal cortex (OFC) (35), and we recently showed (36) that an intact amygdala is required to protect us from illusory body experiences and distortions in self-perception. Interestingly, lesions of the basolateral amygdala hinder the formation of stimulus-outcome representations in the OFC of rats (37) and amygdala lesions in macaques significantly reduced, but did not abolish, the encoding of reward value in the OFC (38). Amygdala lesions in humans have also been found to result in reduced OFC activation associated with reward expectation (39). In the present study, at baseline, A.M. exhibited increased connectivity between the SAN and the precuneus, a functional core of the DMN. It has been found that structural integrity of the SAN is necessary for the efficient regulation of activity in the DMN (40). Thus, amygdala damage may affect the homeostatic interplay between large-scale networks (20), possibly facilitating hyperconnectivity within the DMN and leading to the self-centered, ruminative responding characteristic of major depression.
The recent discovery of rapid antidepressant effects of ketamine has stimulated a reconceptualization of how treatment-resistant major depression and suicidality could be targeted, but the mechanisms of action of ketamine remain obscure (26). Ketamine infusions in patients with treatment-resistant major depression have been found to induce an increase in glucose metabolism in the prefrontal cortex that correlates with the opposite effect in the amygdala (27). These changes could be causally involved in the antidepressant effect or a by-product of the symptom reduction. Interestingly, in mouse models of depression, infusion of ketamine into the amygdala was found to have no effects (28), while a subanesthetic intraperitoneal dose of ketamine normalized depressive-like behavior and was accompanied by reduced glutamate functional connectivity strength (29). In patients with major depression, ketamine was found to normalize insular connectivity with the DMN (30) and to increase global connectivity in the prefrontal cortex (31).
In the case of A.M., ketamine was able to initiate a rapid antidepressant effect that was associated with a reduction in connectivity between the DMN and SAN, and an enhancement of connectivity between the DMN and FPN (Figure 1). However, these findings should be interpreted cautiously given the limitations of an open-label case study and A.M.’s unique depression phenotype and brain lesion. While A.M. has complete destruction of the basolateral amygdala, we cannot rule out the possibility that functional residual tissue in the central amygdala and the amygdalo-hippocampal transition zone or damage to fibers passing through the calcified regions contributed to the observed results. Furthermore, it is conceivable that ketamine’s effect on functional connectivity was altered by A.M.’s amygdala pathology, making the fMRI findings highly specific to A.M.’s brain.
The case of A.M. illustrates that treatment-resistant major depression can develop despite focal bilateral amygdala damage, highlighting the fact that the amygdala is not necessary for the subjective experience or behavioral presentation of clinical depression. Current conceptions of major depression emphasize heterogeneity in clinical phenotypes (41) and underlying biotypes (42–44), such that amygdala-based biomarkers may prove insightful for some but not all subtypes of the illness. Moreover, consistent with A.M.’s amygdala lesion, her major depression phenotype was characterized by marked anhedonia and cognitive biases but only modest symptoms of anxiety (45). Given the broad spectrum of major depression phenotypes, it is conceivable that the antidepressant effect of ketamine in subgroups of patients with major depression with strong anxiety features or comorbidities may act via amygdala-dependent mechanisms, but our observations show that ketamine can rapidly exert its antidepressant effects with or without the amygdala.
Acknowledgments
The authors thank Petra Broich, M.D., and Michael Trauscheid, M.D., for their generous support in inpatient treatment. They also thank the Brain and Behavior Research Foundation for a NARSAD Young Investigator Grant (to Dr. Feinstein). Dr. Scheele and Dr. Hurlemann are supported by a German Research Foundation grant (SCHE 1913/5-1 and HU 1302/11-1), a German-Israel Foundation for Scientific Research and Development grant (I-1428-105.4/2017), and an Else-Kröner-Fresenius-Stiftung grant (2017_A35).
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Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
Division of Medical Psychology (Scheele, Zimbal, Mielacher, Hurlemann), Department of Anesthesiology (Delis, Neumann), and Department of Psychiatry (Philipsen, Hurlemann), University Hospital, Bonn, Germany; Laureate Institute for Brain Research, Tulsa, Okla. (Feinstein); and Department of Psychiatry, University of Oldenburg Medical Campus, Bad Zwischenahn, Germany (Hurlemann).
The authors report no financial relationships with commercial interests.
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