Vagus nerve stimulation for depression: efficacy and safety in a European study

Background Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. Method An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. Results The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). Conclusions VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European stud

Epidemiology of major depression: how is the view changing ?

Depression refers to a set of prevalent (Kessler et al. 1994), extremely debilitating disorders (Murray and Lopez 1997) that can be characterized by a triad of symptoms: extreme anhedonia (complete loss of pleasure from previously pleasurable activities), depressed mood, and low energy. Other cognitive symptoms (e.g., pessimistic thoughts, feelings of guilt, low self-esteem and suicidal ideations) and somatic symptoms (e.g., sleep and psychomotor disturbances, food-intake and body-weight dysregulation) are also often present. Unipolar major depression is the leading cause of disability worldwide; a contribution almost three times that of chronic obstructive pulmonary disease (Lopez and Murray 1998). Depression is associated with a high mortality due to suicide (Joukamaa et al. 2001) and increases in mortality in comorbid somatic disorders such as cardiovascular disorders or cancer (Glassman and Shapiro 1998; Wulsin et al. 1999). Neuroscientific research in the last decade has led to a more complete conceptualization of depression as a complex interaction of genetic susceptibility and environmental factors (Berton et al. 2006; Berton and Nestler 2006; Nestler et al. 2002; Svenningsson et al 2006; Wong and Licinio 2001). Traditional methods of alleviating depression largely stem from serendipitous observations of antidepressant effects of substances such as iproniazid (originally developed as a treatment for tuberculosis) or imipramine (originally developed as a treatment for schizophrenia). In particular, increasing levels of monoamine neurotransmitters in the synaptic cleft are associated with improvements of depressive symptoms. This insight led to a more targeted drug discovery process, resulting in drugs with fewer side effects, such as SSRI's. A better understanding of the phal (Nemeroff et al. 1996; Richelson 2003; Roose and Schatzberg 2005). These medication treatments, in conjunction with certain methods of psychotherapy, are effective at alleviating depressive symptomatology in most patients. However, these treatments do not work for all patients. A sizable minority of patients does not respond. Indeed, 17−21% of patients suffering from major depression have a poor outcome after two years, and 8−13% have a poor outcome even after five years of treatment (Winokur et al. 1993). These patients thus do not respond to any known treatment combination including electroconvulsive therapy, and are thus referred to as "treatment resistant" patients. This underserved population has had little hope of recovering from this disease. Psychotropic drugs work by altering neurochemistry to a large extent in widespread regions of the brain, many of which may be unrelated to depression. It might be that more focused, targeted treatment approaches that modulate specific networks in the brain will prove a more effective approach to help treatment-resistant patients. In other words, whereas existing depression treatments approach this disease as a general brain dysfunction, a more complete and appropriate treatment will arise from thinking of depression as a dysfunction of specific brain networks that mediate mood and reward signals, in particular, the cortical-limbic- thalamic-striatal network (Mayberg 2002). This conceptualization leads to novel ideas about targeted neuromodulatory treatments which have been researched in the last decade

Nuclei accumbens phase synchrony predicts decision-making reversals following negative feedback

The nucleus accumbens plays a key role in reinforcement-guided behaviors. Here, we report that electrophysiological oscillatory phase synchrony between the two nuclei accumbens may play a crucial role in using negative feedback to guide decision making. We recorded local field potentials from the human nucleus accumbens and the medial frontal cortex (via surface EEG) from patients who had deep brain stimulation electrodes implanted. Patients performed a reversal learning task in which they decided whether to alter their decision strategy following monetary losses. Strategy switches following losses were preceded by enhanced theta (4-8 Hz) phase synchrony between the nuclei accumbens, and a break-down of gamma (20-80 Hz)- (8-12 Hz) coupling. Furthermore, the strength of the intersite phase synchrony predicted response time adjustments in the subsequent trial. These findings suggest that a neural network including the nucleus accumbens bilaterally becomes functionally connected via theta phase synchrony to signal the need to adjust behavior

Intracranial EEG correlates of expectancy and memory formation in the human hippocampus and nucleus accumbens

SummaryThe human brain is adept at anticipating upcoming events, but in a rapidly changing world, it is essential to detect and encode events that violate these expectancies. Unexpected events are more likely to be remembered than predictable events, but the underlying neural mechanisms for these effects remain unclear. We report intracranial EEG recordings from the hippocampus of epilepsy patients, and from the nucleus accumbens of depression patients. We found that unexpected stimuli enhance an early (187 ms) and a late (482 ms) hippocampal potential, and that the late potential is associated with successful memory encoding for these stimuli. Recordings from the nucleus accumbens revealed a late potential (peak at 475 ms), which increases in magnitude during unexpected items, but no subsequent memory effect and no early component. These results are consistent with the hypothesis that activity in a loop involving the hippocampus and the nucleus accumbens promotes encoding of unexpected events

The N-Methyl-D-Aspartate Receptor Co-agonist D-Cycloserine Facilitates Declarative Learning and Hippocampal Activity in Humans

The N-methyl-D-aspartate receptor (NMDAR) is critical for learning-related synaptic plasticity in amygdala and hippocampus. As a consequence, there is considerable interest in drugs targeting this receptor to help enhance amygdala- and hippocampus-dependent learning. A promising candidate in this respect is the NMDAR glycine-binding site partial agonist D-cycloserine (DCS). Accumulating clinical evidence indicates the efficacy of DCS in the facilitation of amygdala-dependent fear extinction learning in patients with phobic, social anxiety, panic, and obsessive-compulsive disorder. An important unresolved question though is whether the use of DCS can also facilitate hippocampus-dependent declarative learning in healthy people as opposed to being restricted to the fear memory domain.In the present study, we investigated whether or not DCS can facilitate hippocampus-dependent declarative learning. We have therefore combined functional magnetic resonance imaging with two different declarative learning tasks and cytoarchitectonic probabilistic mapping of the hippocampus and its major subdivisions in 40 healthy volunteers administered either a 250 mg single oral dose of DCS or a placebo.We found that DCS facilitates declarative learning as well as blood-oxygen level dependent activity levels in the probabilistically defined cornu ammonis region of the hippocampus. The absence of activity changes in visual control areas underscores the specific action of DCS in the hippocampal cornu ammonis region.Our findings highlight NMDAR glycine-binding site partial agonism as a promising pharmacological mechanism for facilitating declarative learning in healthy people

Nucleus Accumbens Deep Brain Stimulation Decreases Ratings of Depression and Anxiety in Treatment-Resistant Depression

While most patients with depression respond to combinations of pharmacotherapy, psychotherapy, and electroconvulsive therapy (ECT), there are patients requiring other treatments. Deep brain stimulation (DBS) allows modulation of brain regions that are dysfunctional in depression. Since anhedonia is a feature of depression and there is evidence of dysfunction of the reward system, DBS to the nucleus accumbens (NAcc) might be promising.Ten patients suffering from very resistant forms of depression (treatment-resistant depression [TRD]), not responding to pharmacotherapy, psychotherapy, or ECT, were implanted with bilateral DBS electrodes in the NAcc. The mean (+/-SD) length of the current episode was 10.8 (+/-7.5) years; the number of past treatment courses was 20.8 (+/-8.4); and the mean Hamilton Depression Rating Scale (HDRS) was 32.5 (+/-5.3).Twelve months following initiation of DBS treatment, five patients reached 50% reduction of the HDRS (responders, HDRS = 15.4 [+/-2.8]). The number of hedonic activities increased significantly. Interestingly, ratings of anxiety (Hamilton Anxiety Scale) were reduced in the whole group but more pronounced in the responders. The [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography data revealed that NAcc-DBS decreased metabolism in the subgenual cingulate and in prefrontal regions including orbital prefrontal cortex. A volume of interest analysis comparing responders and nonresponders identified metabolic decreases in the amygdala.We demonstrate antidepressant and antianhedonic effects of DBS to NAcc in patients suffering from TRD. In contrast to other DBS depression studies, there was also an antianxiety effect. These effects are correlated with localized metabolic changes

Fear Processing and Social Networking in the Absence of a Functional Amygdala

The human amygdala plays a crucial role in processing social signals, such as face expressions, particularly fearful ones, and facilitates responses to them in face-sensitive cortical regions. This contributes to social competence and individual amygdala size correlates with that of social networks. While rare patients with focal bilateral amygdala lesion typically show impaired recognition of fearful faces, this deficit is variable, and an intriguing possibility is that other brain regions can compensate to support fear and social signal processing.To investigate the brain's functional compensation of selective bilateral amygdala damage, we performed a series of behavioral, psychophysiological, and functional magnetic resonance imaging experiments in two adult female monozygotic twins (patient 1 and patient 2) with equivalent, extensive bilateral amygdala pathology as a sequela of lipoid proteinosis due to Urbach-Wiethe disease.Patient 1, but not patient 2, showed preserved recognition of fearful faces, intact modulation of acoustic startle responses by fear-eliciting scenes, and a normal-sized social network. Functional magnetic resonance imaging revealed that patient 1 showed potentiated responses to fearful faces in her left premotor cortex face area and bilaterally in the inferior parietal lobule.The premotor cortex face area and inferior parietal lobule are both implicated in the cortical mirror-neuron system, which mediates learning of observed actions and may thereby promote both imitation and empathy. Taken together, our findings suggest that despite the pre-eminent role of the amygdala in processing social information, the cortical mirror-neuron system may sometimes adaptively compensate for its pathology