Behavioral and cortical arousal from sleep, muscimol-induced coma, and anesthesia by direct optogenetic stimulation of cortical neurons.

The cerebral cortex is widely considered part of the neural substrate of consciousness, but direct causal evidence is missing. Here, we tested in mice whether optogenetic activation of cortical neurons in posterior parietal cortex (PtA) or medial prefrontal cortex (mPFC) is sufficient for arousal from three behavioral states characterized by progressively deeper unresponsiveness: sleep, a coma-like state induced by muscimol injection in the midbrain, and deep sevoflurane-dexmedetomidine anesthesia. We find that cortical stimulation always awakens the mice from both NREM sleep and REM sleep, with PtA requiring weaker/shorter light pulses than mPFC. Moreover, in most cases light pulses produce both cortical activation (decrease in low frequencies) and behavioral arousal (recovery of the righting reflex) from brainstem coma, as well as cortical activation from anesthesia. These findings provide evidence that direct activation of cortical neurons is sufficient for behavioral and/or cortical arousal from sleep, brainstem coma, and anesthesia.

A Quality Improvement Curriculum for Psychiatry Residents.

Introduction: Quality improvement (QI) is an increasingly important aspect of health care and residency education. There is relatively little research describing QI curricula for residents in psychiatry. Although QI curricula have been published in MedEdPORTAL, the current resource represents the first such curriculum specific to psychiatry residents. This resource aims to present a QI curriculum for psychiatry residents. Methods: The University of Wisconsin psychiatry residency program implemented a QI curriculum for our PGY 3 psychiatry residents in 2010. The initial version of the curriculum has undergone marked changes over the ensuing years, reflecting feedback received from learners and faculty instructors, as well as ongoing review of the literature, to ascertain best practices in this area of medical education. Steps taken have included faculty training, development of evaluation forms, and implementation of elements to increase accountability for successful, sustainable project development. Results: During the 8 completed years of this curriculum, 77 PGY 3 psychiatry residents have completed it. The Quality Improvement Knowledge Application Tool adapted for psychiatry was completed by PGY 3 residents in advance of and upon completion of the curriculum for the first 2 years of the curriculum; results demonstrated a significant improvement in scores as a measurement of QI knowledge and skills. Thirty-one of 32 resident teams (97%) have implemented a QI project. Discussion: Our QI curriculum for PGY 3 psychiatry residents has been successful in equipping residents with QI knowledge and having them implement QI projects.

'Medical Clearance' of Patients With Acute Mental Health Needs in the Emergency Department: A Literature Review and Practice Recommendations.

INTRODUCTION: Emergency departments have seen increasing numbers of patients presenting with acute mental illness. Currently, there is not a standard for assessing the medical stability of these patients prior to transfer to inpatient psychiatric services, which causes unnecessary delays in patient care. OBJECTIVE: Provide a literature review and multidisciplinary expert consensus recommendations to simplify and expedite the medical evaluation of patients requiring admission to inpatient psychiatric facilities. METHODS: A task force with representation from emergency physicians (Wisconsin Chapter of the American College of Emergency Physicians) and psychiatrists (Wisconsin Psychiatric Association) met to create this position statement. The members reviewed clinical practice guidelines and primary literature sources to develop evidence-based recommendations. RESULTS: Five categories of recommendations were developed: (1) A detailed history and physical exam should constitute the minimum necessary information required for most medical assessments. (2) Clinical information should guide further diagnostic testing; therefore, receiving facility blanket requirements for routine testing should be abandoned. (3) Emergency physicians should understand the limited medical capabilities of institutes of mental disease. Obtaining reasonable diagnostic testing that is not available at these facilities may be appropriate, though this should not delay patient transfer. (4) Structured medical evaluation algorithms should be used to enhance the uniformity of medical assessments for these patients. This task force recommends the Wisconsin SMART Form. (5) Emergency physicians and psychiatrists should communicate more regularly without intermediaries, both at the clinical encounter and beyond. CONCLUSION: The recommendations in this paper are endorsed by the Wisconsin Chapter of the American College of Emergency Physicians and the Wisconsin Psychiatric Association, which strongly urge affected medical providers to adopt them into routine practice.

A Curriculum for Residents to Develop Successful Quality Improvement Projects.

BACKGROUND: Quality improvement (QI) education in residency training has become critical for numerous reasons, but little has been written about factors that lead to successful improvement projects within residency training. METHODS: A quality improvement curriculum for third-year psychiatry residents was developed. The percentage of resident projects that have been successfully implemented was calculated. Residents completed the QI Knowledge Application Tool adapted for psychiatry before and after the curriculum to assess knowledge and skills. RESULTS: Eighteen of 19 resident projects were successfully implemented. QI Knowledge Application Tool scores improved from 4.8 to 8.1 (P = 0.0053) after completion of the curriculum. CONCLUSIONS: Residents are able to implement successful projects and to increase their knowledge and skills in quality improvement when given appropriate resources and incentives.

A Review of Posttraumatic Stress Disorder and Obesity: Exploring the Link.

OBJECTIVE: The incidence of posttraumatic stress disorder (PTSD) and obesity are on the rise, and evidence continues to support the observation that individuals who have symptoms of PTSD are more likely to develop obesity in their lifetime. The incidence of obesity in individuals with PTSD, including war veterans, women, and children exposed to trauma, is not solely attributable to psychotropic medications, but actual pathophysiologic mechanisms have not been fully delineated. Additionally, there are no studies to date demonstrating that obese individuals are predisposed to developing PTSD compared to the general population. This review explores the pathogenic pathways common to both PTSD and obesity, which include inflammation, the renin-angiotensin-aldosterone system, cellular structures, and neuroendocrine activation. DATA SOURCES AND SYNTHESIS: A PubMed search for the years 2000-2015 with the keywords PTSD and obesity was performed. There were no language restrictions. RESULTS: More research is needed in human subjects to understand the pathogenic pathways common to both PTSD and obesity and to further clarify the direction of identified associations. Ideally, in the future, clinical interventions targeting these pathways may be able to modify the course of PTSD and obesity. The outcome of studies investigating the utility of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the treatment of PTSD symptoms will be relevant to control both PTSD and obesity. Importantly, outcomes assessing inflammation, obesity, and cardiac function in the same subjects also should be determined. CONCLUSION: Research is needed to reveal the multidimensional and intricate relationship between PTSD and obesity. The implications of this research would be essential for treatment, prevention, and potential public health reforms.

Effects of partial sleep deprivation on slow waves during non-rapid eye movement sleep: A high density EEG investigation.

OBJECTIVE: Changes in slow waves during non-rapid eye movement (NREM) sleep in response to acute total sleep deprivation are well-established measures of sleep homeostasis. This investigation utilized high-density electroencephalography (hdEEG) to examine topographic changes in slow waves during repeated partial sleep deprivation. METHODS: Twenty-four participants underwent a 6-day sleep restriction protocol. Spectral and period-amplitude analyses of sleep hdEEG data were used to examine changes in slow wave energy, count, amplitude, and slope relative to baseline. RESULTS: Changes in slow wave energy were dependent on the quantity of NREM sleep utilized for analysis, with widespread increases during sleep restriction and recovery when comparing data from the first portion of the sleep period, but restricted to recovery sleep if the entire sleep episode was considered. Period-amplitude analysis was less dependent on the quantity of NREM sleep utilized, and demonstrated topographic changes in the count, amplitude, and distribution of slow waves, with frontal increases in slow wave amplitude, numbers of high-amplitude waves, and amplitude/slopes of low amplitude waves resulting from partial sleep deprivation. CONCLUSIONS: Topographic changes in slow waves occur across the course of partial sleep restriction and recovery. SIGNIFICANCE: These results demonstrate a homeostatic response to partial sleep loss in humans.

Altered prefrontal activity and connectivity predict different cognitive deficits in schizophrenia.

BACKGROUND: Cognitive dysfunction is considered a core feature of schizophrenia, and impaired performances in episodic memory (EM) and executive function (EF) tasks are consistently reported in schizophrenia patients. Traditional fMRI and EEG studies have helped identifying brain areas, including the prefrontal cortex (PFC), involved in these tasks. However, it is unclear whether intrinsic defects in prefrontal function per se contribute to poor performance in schizophrenia, given the presence of confounds like reduced motivation and psychotic symptoms. TMS/hd-EEG measurements are obtained without cognitive effort, and can be calculated in any cortical area. METHODS: We performed TMS/hd-EEG recordings in parietal, motor, premotor, and PFC in healthy individuals (N=20) and schizophrenia patients (N=20). Source modeling of TMS-evoked responses was performed, and measures of cortical activity (significant current density, SCD) and connectivity (significant current scattering, SCS) were computed. Patients with schizophrenia also performed Penn Word memory delayed (CPWd) and Penn Conditional Exclusion Test (PCET). CPWd evaluates EM and involves primarily PFC, whereas PCET reflects EF and implicates PFC with other brain regions. FINDINGS: We found no difference in SCD and SCS after TMS of parietal/motor cortices, whereas those parameters were reduced in premotor/prefrontal areas in schizophrenia patients. In PFC, where these measures were most defective, SCD was negatively correlated with performance in CPWd whereas higher SCS values were associated with more errors in PCET. CONCLUSION: These findings indicate that schizophrenia patients have intrinsic defects in both activity and connectivity of PFC, and that these defects are specifically associated with impairments in cognitive abilities.

Topographic deficits in alpha-range resting EEG activity and steady state visual evoked responses in schizophrenia.

Deficits in both resting alpha-range (8-12Hz) electroencephalogram (EEG) activity and steady state evoked potential (SSVEP) responses have been reported in schizophrenia. However, the topographic specificity of these effects, the relationship between resting EEG and SSVEP, as well as the impact of antipsychotic medication on these effects, have not been clearly delineated. The present study sought to address these questions with 256 channel high-density EEG recordings in a group of 13 schizophrenia patients, 13 healthy controls, and 10 non-schizophrenia patients with psychiatric diagnoses currently taking antipsychotic medication. At rest, the schizophrenia group demonstrated decreased alpha EEG power in frontal and occipital areas relative to healthy controls. With SSVEP stimulation centered in the alpha band (10Hz), but not with stimulation above (15Hz) or below (7Hz) this range, the occipital deficit in alpha power was partially reverted. However, the frontal deficit persisted and contributed to a significantly reduced topographic relationship between occipital and frontal alpha activity for resting EEG and 10Hz SSVEP alpha power in schizophrenia patients. No significant differences were observed between healthy and medicated controls or between medicated controls and schizophrenia. These findings suggest a potential intrinsic deficit in frontal eyes-closed EEG alpha oscillations in schizophrenia, whereby potent visual stimulation centered in that frequency range results in an increase in the occipital alpha power of these patients, which however does not extend to frontal regions. Future research to evaluate the cortical and subcortical mechanisms of these effects is warranted.

Sleep Disturbances in Depression.

Major depressive disorder is frequently accompanied by sleep disturbances such as insomnia or hypersomnia and polysomnographic sleep findings of increased rapid-eye-movement sleep and decreased slow wave sleep. For many patients, insomnia persists even after mood symptoms have been adequately treated. These patients have poorer outcomes than patients without sleep problems. These outcomes suggest that overlapping neural mechanisms regulate sleep and mood. Treatment of these patients can incorporate sedating antidepressants, nonbenzodiazepine γ-aminobutyric acid agonists, and cognitive behavioral therapy. Sleep restriction has been found to improve mood in depressed patients; however, the benefits typically disappear after recovery sleep.

Neural Correlates of Schizophrenia Negative Symptoms: Distinct Subtypes Impact Dissociable Brain Circuits.

BACKGROUND: The negative symptoms of schizophrenia include deficits in emotional expression and motivation. These deficits are stable over the course of illness and respond poorly to current medications. Previous studies have focused on negative symptoms as a single category; however, individual symptoms might be related to separate neurological disturbances. We analyzed data from the Functional Biomedical Informatics Research Network dataset to explore the relationship between individual negative symptoms and functional brain activity during an auditory oddball task. METHODS: Functional magnetic resonance imaging was conducted on 89 schizophrenia patients and 106 healthy controls during a two-tone auditory oddball task. Blood oxygenation level-dependent (BOLD) signal during the target tone was correlated with severity of five negative symptom domains from the Scale for the Assessment of Negative Symptoms. RESULTS: The severity of alogia, avolition/apathy and anhedonia/asociality was negatively correlated with BOLD activity in distinct sets of brain regions associated with processing of the target tone, including basal ganglia, thalamus, insular cortex, prefrontal cortex, posterior cingulate and parietal cortex. CONCLUSIONS: Individual symptoms were related to different patterns of functional activation during the oddball task, suggesting that individual symptoms might arise from distinct neural mechanisms. This work has potential to inform interventions that target these symptom-related neural disruptions.

Reduced mediodorsal thalamic volume and prefrontal cortical spindle activity in schizophrenia.

BACKGROUND: We recently found marked deficits in sleep spindles, non-rapid eye movement (NREM) sleep oscillations that are generated within the thalamus and then amplified and sustained in the cortex, in patients with schizophrenia compared to both healthy and psychiatric controls. Here, we investigated the thalamic and cortical contributions to these sleep spindle deficits. METHODS: Anatomical volume of interest analysis (i.e., thalamic volumes) and electroencephalogram (EEG) source modeling (i.e., spindle-related cortical currents) were performed in patients with schizophrenia and healthy comparison subjects. FINDINGS: Schizophrenia patients had reduced mediodorsal (MD) thalamic volumes, especially on the left side, compared to healthy controls, whereas whole thalami and lateral geniculate nuclei did not differ between groups. Furthermore, left MD volumes were strongly correlated with the number of scalp-recorded spindles in an anterior frontal region, and cortical currents underlying these anterior frontal spindles were localized in the prefrontal cortex, in Brodmann area (BA) 10. Finally, prefrontal currents at the peak of spindle activity were significantly reduced in schizophrenia patients and correlated with their performance in an abstraction/working memory task. CONCLUSION: Altogether, these findings point to deficits in a specific thalamo-cortical circuitry in schizophrenia, which is associated with some cognitive deficits commonly reported in those patients.

Increased prefrontal cortex activity during negative emotion regulation as a predictor of depression symptom severity trajectory over 6 months.

IMPORTANCE: Emotion regulation is critically disrupted in depression, and the use of paradigms that tap into these processes may uncover essential changes in neurobiology during treatment. In addition, because neuroimaging outcome studies of depression commonly use only baseline and end-point data-which are more prone to week-to-week noise in symptomatology-we sought to use all data points over the course of a 6-month trial. OBJECTIVE: To examine changes in neurobiology resulting from successful treatment. DESIGN, SETTING, AND PARTICIPANTS: Double-blind trial examining changes in the neural circuits involved in emotion regulation resulting from 1 of 2 antidepressant treatments during a 6-month trial. Twenty-one patients with major depressive disorder and without other Axis I or Axis II diagnoses were scanned before treatment and 2 and 6 months into treatment at the university's functional magnetic resonance imaging facility. INTERVENTIONS: Venlafaxine hydrochloride extended release (with doses of up to 300 mg) or fluoxetine hydrochloride (with doses of up to 80 mg). MAIN OUTCOMES AND MEASURES: Neural activity, as measured using functional magnetic resonance imaging during performance of an emotion regulation paradigm, as well as regular assessments of symptom severity using the Hamilton Depression Rating Scale. For use of all data points, slope trajectories were calculated for rate of change in depression severity and for rate of change in neural engagement. RESULTS: The depressed individuals who showed the steepest decrease in depression severity over the 6-month period were the same individuals who showed the most rapid increases in activity in Brodmann area 10 and the right dorsolateral prefrontal cortex activity when regulating negative affect over the same time frame. This relationship was more robust when using only the baseline and end-point data. CONCLUSIONS AND RELEVANCE: Changes in prefrontal cortex engagement when regulating negative affect correlate with changes in depression severity over 6 months. These results are buttressed by calculating these statistics, which are more reliable and robust to week-to-week variation than are difference scores.

Relationships between changes in sustained fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment.

OBJECTIVE Deficits in positive affect and their neural bases have been associated with major depression. However, whether reductions in positive affect result solely from an overall reduction in nucleus accumbens activity and fronto-striatal connectivity or the additional inability to sustain engagement of this network over time is unknown. The authors sought to determine whether treatment-induced changes in the ability to sustain nucleus accumbens activity and fronto-striatal connectivity during the regulation of positive affect are associated with gains in positive affect. METHOD Using fMRI, the authors assessed the ability to sustain activity in reward-related networks when attempting to increase positive emotion during performance of an emotion regulation paradigm in 21 depressed patients before and after 2 months of antidepressant treatment. Over the same interval, 14 healthy comparison subjects underwent scanning as well. RESULTS After 2 months of treatment, self-reported positive affect increased. The patients who demonstrated the largest increases in sustained nucleus accumbens activity over the 2 months were those who demonstrated the largest increases in positive affect. In addition, the patients who demonstrated the largest increases in sustained fronto-striatal connectivity were also those who demonstrated the largest increases in positive affect when controlling for negative affect. None of these associations were observed in healthy comparison subjects. CONCLUSIONS Treatment-induced change in the sustained engagement of fronto-striatal circuitry tracks the experience of positive emotion in daily life. Studies examining reduced positive affect in a variety of psychiatric disorders might benefit from examining the temporal dynamics of brain activity when attempting to understand changes in daily positive affect.

Sex-related differences in sleep slow wave activity in major depressive disorder: a high-density EEG investigation.

BACKGROUND: Sleep disturbance plays an important role in major depressive disorder (MDD). Prior investigations have demonstrated that slow wave activity (SWA) during sleep is altered in MDD; however, results have not been consistent across studies, which may be due in part to sex-related differences in SWA and/or limited spatial resolution of spectral analyses. This study sought to characterize SWA in MDD utilizing high-density electroencephalography (hdEEG) to examine the topography of SWA across the cortex in MDD, as well as sex-related variation in SWA topography in the disorder. METHODS: All-night recordings with 256 channel hdEEG were collected in 30 unipolar MDD subjects (19 women) and 30 age and sex-matched control subjects. Spectral analyses of SWA were performed to determine group differences. SWA was compared between MDD and controls, including analyses stratified by sex, using statistical non-parametric mapping to correct for multiple comparisons of topographic data. RESULTS: As a group, MDD subjects demonstrated significant increases in all-night SWA primarily in bilateral prefrontal channels. When stratified by sex, MDD women demonstrated global increases in SWA relative to age-matched controls that were most consistent in bilateral prefrontal regions; however, MDD men showed no significant differences relative to age-matched controls. Further analyses demonstrated increased SWA in MDD women was most prominent in the first portion of the night. CONCLUSIONS: Women, but not men with MDD demonstrate significant increases in SWA in multiple cortical areas relative to control subjects. Further research is warranted to investigate the role of SWA in MDD, and to clarify how increased SWA in women with MDD is related to the pathophysiology of the disorder.

Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia.

CONTEXT: Converging evidence from electrophysiological studies suggests that in individuals with schizophrenia, electroencephalographic frontal fast oscillations are reduced. It is still unclear whether this reduction reflects an intrinsic deficit of underlying cortical/thalamocortical circuits and whether this deficit is specific for frontal regions. Recent electrophysiological studies in healthy individuals have established that, when perturbed, different brain regions oscillate at a specific, intrinsically generated dominant frequency, the natural frequency. OBJECTIVE: To assess the natural frequency of the posterior parietal, motor, premotor, and prefrontal cortices in patients with schizophrenia and healthy control subjects. DESIGN: High-density electroencephalographic recordings during transcranial magnetic stimulation of 4 cortical areas were performed. Several transcranial magnetic stimulation­evoked electroencephalographic oscillation parameters, including synchronization, amplitude, and natural frequency, were compared across the schizophrenia and healthy control groups. SETTING: Wisconsin Psychiatric Institute and Clinic, University of Wisconsin­Madison. PARTICIPANTS: Twenty patients with schizophrenia and 20 age-matched healthy control subjects. MAIN OUTCOME MEASURES: High-density electroencephalographic measurements of transcranial magnetic stimulation­evoked activity in 4 cortical areas, scores on the Positive and Negative Syndrome Scale, and performance scores (reaction time, accuracy) on 2 computerized tasks (word memory [Penn Word Recognition Test] and facial memory [Penn Facial Memory Test]). RESULTS: Patients with schizophrenia showed a slowing in the natural frequency of the frontal/prefrontal regions compared with healthy control subjects (from an average of a 2-Hz decrease for the motor area to an almost 10-Hz decrease for the prefrontal cortex). The prefrontal natural frequency of individuals with schizophrenia was slower than in any healthy comparison subject and correlated with both positive Positive and Negative Syndrome Scale scores and reaction time on the Penn Word Recognition Test. CONCLUSIONS: These findings suggest that patients with schizophrenia have an intrinsic slowing in the natural frequency of frontal cortical/thalamocortical circuits, that this slowing is not present in parietal areas, and that the prefrontal natural frequency can predict some of the symptoms as well as the cognitive dysfunctions of schizophrenia.

Altered slow wave activity in major depressive disorder with hypersomnia: a high density EEG pilot study.

Hypersomnolence in major depressive disorder (MDD) plays an important role in the natural history of the disorder, but the basis of hypersomnia in MDD is poorly understood. Slow wave activity (SWA) has been associated with sleep homeostasis, as well as sleep restoration and maintenance, and may be altered in MDD. Therefore, we conducted a post-hoc study that utilized high density electroencephalography (hdEEG) to test the hypothesis that MDD subjects with hypersomnia (HYS+) would have decreased SWA relative to age- and sex-matched MDD subjects without hypersomnia (HYS-) and healthy controls (n=7 for each group). After correction for multiple comparisons using statistical non-parametric mapping, HYS+ subjects demonstrated significantly reduced parieto-occipital all-night SWA relative to HYS- subjects. Our results suggest hypersomnolence may be associated with topographic reductions in SWA in MDD. Further research using an adequately powered prospective design is indicated to confirm these findings.

Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging.

CONTEXT: Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method. OBJECTIVE: To test the hypothesis that direct physiological stimulation of the cortex will produce an abnormal thalamic response in individuals with schizophrenia. DESIGN: We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically connected regions (thalamus, medial superior frontal cortex, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 gamma functions, and response parameters were compared across groups. SETTING: Academic research laboratory. PARTICIPANTS: Patients with schizophrenia and sex- and age-matched psychiatrically healthy subjects were recruited from the community. MAIN OUTCOME MEASURE: Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus. RESULTS: The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with control subjects. CONCLUSIONS: Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.

Reduced right ventrolateral prefrontal cortex activity while inhibiting positive affect is associated with improvement in hedonic capacity after 8 weeks of antidepressant treatment in major depressive disorder.

BACKGROUND: Anhedonia, a reduced ability to experience pleasure, is a chief symptom of major depressive disorder and is related to reduced frontostriatal connectivity when attempting to upregulate positive emotion. The present study examined another facet of positive emotion regulation associated with anhedonia-namely, the downregulation of positive affect-and its relation to prefrontal cortex (PFC) activity. METHODS: Neuroimaging data were collected from 27 individuals meeting criteria for major depressive disorder as they attempted to suppress positive emotion during a positive emotion regulation task. Their PFC activation pattern was compared with the PFC activation pattern exhibited by 19 healthy control subjects during the same task. Anhedonia scores were collected at three time points: at baseline (time 1), 8 weeks after time 1 (i.e., time 2), and 6 months after time 1 (i.e., time 3). Prefrontal cortex activity at time 1 was used to predict change in anhedonia over time. Analyses were conducted utilizing hierarchical linear modeling software. RESULTS: Depressed individuals who could not inhibit positive emotion-evinced by reduced right ventrolateral prefrontal cortex activity during attempts to dampen their experience of positive emotion in response to positive visual stimuli-exhibited a steeper anhedonia reduction slope between baseline and 8 weeks of treatment with antidepressant medication (p < .05). Control subjects showed a similar trend between baseline and time 3. CONCLUSIONS: To reduce anhedonia, it may be necessary to teach individuals how to counteract the functioning of an overactive pleasure-dampening prefrontal inhibitory system.