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Accelerated TMS is an emerging application of Transcranial Magnetic Stimulation (TMS) aimed to reduce treatment length and improve response time. Extant literature generally shows similar efficacy and safety profiles compared to the FDA-cleared protocols for TMS to treat major depressive disorder (MDD), yet accelerated TMS research remains at a very early stage in development. The few applied protocols have not been standardized and vary significantly across a set of core elements. In this review, we consider nine elements that include treatment parameters (i.e., frequency and inter-stimulation interval), cumulative exposure (i.e., number of treatment days, sessions per day, and pulses per session), individualized parameters (i.e., treatment target and dose), and brain state (i.e., context and concurrent treatments). Precisely which of these elements is critical and what parameters are most optimal for the treatment of MDD remains unclear. Other important considerations for accelerated TMS include durability of effect, safety profiles as doses increase over time, the possibility and advantage of individualized functional neuronavigation, use of biological readouts, and accessibility for patients most in need of the treatment. Overall, accelerated TMS appears to hold promise to reduce treatment time and achieve rapid reduction in depressive symptoms, but at this time significant work remains to be done. Rigorous clinical trials combining clinical outcomes and neuroscientific measures such as electroencephalogram, magnetic resonance imaging and e-field modeling are needed to define the future of accelerated TMS for MDD.

The ventral striatum is believed to encode the subjective value of cost-benefit options; however, this effect has notably been absent during choices that involve physical effort. Previous work in freely moving animals has revealed opposing striatal signals, with greater response to increasing effort demands and reduced responses to rewards requiring effort. Yet, the relationship between these conflicting signals remains unknown. Using functional magnetic resonance imaging with a naturalistic maze-navigation paradigm, we identified functionally segregated regions within the ventral striatum that separately encoded effort activation, movement initiation and effort discounting of rewards. In addition, activity in regions associated with effort activation and discounting oppositely predicted striatal encoding of effort during effort-based decision-making. Our results suggest that the dorsomedial region hitherto associated with action may instead represent the cost of effort and raise fundamental questions regarding the interpretation of striatal 'reward' signals in the context of effort demands. This has implications for uncovering the neural architecture underlying motivated behaviour.

The ventral striatum is believed to encode the subjective value of cost/benefit options; however, this effect has strikingly been absent during choices that involve physical effort. Prior work in freely-moving animals has revealed opposing striatal signals, with greater response to increasing effort demands and reduced responses to rewards requiring effort. Yet, the relationship between these conflicting signals remains unknown. Using fMRI with a naturalistic, effort-based navigation paradigm, we identified functionally-segregated regions within ventral striatum that separately encoded action, effort, and discounting of rewards by effort. Strikingly, these sub-regions mirrored results from a large-sample connectivity-based parcellation of the striatum. Moreover, individual differences in striatal effort activation and effort discounting signals predicted striatal responses to effort-related choices during an independent fMRI task. Taken together, our results suggest that a dorsomedial region primarily associated with action may instead represent the effort cost of actions, and raises fundamental questions regarding the interpretation of striatal “reward” signals in the context of effort demands.

Investigations of pathophysiological mechanisms implicated in vulnerability to depression have been negatively impacted by the significant heterogeneity characteristic of psychiatric syndromes. Such challenges are also reflected in numerous null findings emerging from genome-wide association studies (GWAS) of depression. Bolstered by increasing sample sizes, recent GWAS studies have identified genetics variants linked to MDD. Among them, Okbay and colleagues (Nat. Genet. 2016 Jun;48(6):624–33) identified genetic variants associated with three well-validated depression-related phenotypes: subjective well-being, depressive symptoms, and neuroticism. Despite this progress, little is known about psychopathological and neurobiological mechanisms underlying such risk. To fill this gap, a genetic risk score (GRS) was computed from the Okbay’s study for a sample of 88 psychiatrically healthy females. Across two sessions, participants underwent two well-validated psychosocial stressors, and performed two separate tasks probing reward learning both before and after stress. Analyses tested whether GRS scores predicted anhedonia-related phenotypes across three units of analyses: self-report (Snaith Hamilton Pleasure Scale), behavior (stress-induced changes in reward learning), and circuits (stress-induced changes in striatal reward prediction error; striatal volume). GRS scores were negatively associated with anhedonia-related phenotypes across all units of analyses but only circuit-level variables were significant. In addition, the amount of explained variance was systematically larger as variables were putatively closer to the effects of genes (self-report

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is a novel therapy for neuropsychiatric disorders. Hypomania is a known complication of VC/VS DBS, but who is at risk is less understood. Factors such as family history, combined with details of DBS programming, might quantify that risk. The authors performed an iterative modeling procedure on a VC/VS DBS patient registry to identify key predictors. Hypomania was less common for men and for patients stimulated on the ventral right contact. It was more common with right monopolar stimulation. These findings may help to establish decision rules to reduce complications of VC/VS DBS.

Anhedonia is a severe condition that describes a near-complete absence of enjoyment, motivation, and interest. A core feature of depression, clinical manifestations of anhedonia can include deficits in experiencing pleasure, approach-related motivated behavior, and learning how to match expectations to the environment. To date, the precise neurobiological mechanisms of anhedonia in major depression are still poorly understood. We have previously argued that contradictory findings and the inability to identify specific neurobiological substrates for anhedonic symptoms may result from sample heterogeneity, suboptimal methods of assessment, and the challenge of dissociating between different components of anhedonia. Recently, however, computational advances to the operationalization of psychiatric symptoms have enhanced the ability to evaluate the neurobiology of constituent elements of this symptom domain. In this paper, we review (1) advances in behavioral and computational methods of assessing reward processing and motivation and (2) the development of new self-report, neurological, and biological methods of subtyping that may be useful in future pursuits to expand our understanding of the neurobiology of anhedonia in depression.

In this monograph, we briefly review the rationale for deep brain stimulation (DBS) for psychiatric illness, beginning with current noninvasive treatment options and progressing to the evolution and success of DBS as a therapy. This discussion will focus on obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) particularly, as these are the only two diagnoses that have been subjected to adequately controlled DBS trials to date. The majority of the essay then describes the significant limitations that DBS is currently facing and emerging approaches to address them. This will lead into a discussion of new technologies such as patient-specific modeling of electric fields and closed-loop DBS systems and how we can best utilize these to increase our understanding of DBS and the overall efficacy of this novel therapy. Keywords: brain stimulation; neuromodulation; neural engineering; stimulations; psychiatry; mental illness; obsessive-compulsive disorder; depression

CME Educational Objectives 1. Provide an overview of the history and origins of deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD). 2. Describe the various neuroanatomic targets of DBS implant for OCD as well as the neurocircuitry involved. 3. Explain the effects of DBS for OCD, both intended and unintended, as well as the promise the treatment holds for select treatment-resistant OCD patients. Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder that affects approximately 2% to 3% of the population. 1 OCD is characterized by persistent, intrusive, and distressing thoughts (obsessions) and ritualistic behaviors (compulsions), such as counting, organizing, or cleaning, which are used to lessen anxiety caused by the obsessive thoughts. The symptoms of OCD generally manifest in childhood or adolescence and may result in significant impairment in everyday functioning. The etiology of OCD is hypothesized to involve a combination of genetic and environmental factors.

CME Educational Objectives 1. Discuss current goals of translational and clinical research in deep brain stimulation (DBS). 2. Identify the clinical disorders currently being explored as new potential targets for DBS. 3. Understand in a clinically relevant manner the methodologic improvements currently in development for DBS. Deep brain stimulation (DBS) is a surgical neuromodulation therapy with several neuropsychiatric applications. The US Food and Drug Administration approved its use in the United States for the treatment of refractory essential tremor (approved in 1997), idiopathic Parkinson’s disease (thalamic stimulation approved in 1997 and subthalamic nucleus and globus pallidus pars interna stimulation in 2002), dystonia (2003), and obsessive-compulsive disorder (OCD; 2009). 1,2 The last two disorders were approved under a humanitarian device exception.

CME Educational Objectives 1. Describe the role of deep brain stimulation (DBS) in treatment-resistant depression (TRD). 2. Identify the current primary brain targets used in DBS for TRD and describe the major clinical findings. 3. Explain the potential future direction of DBS for TRD. Major depressive disorder (MDD) is a psychiatric disorder characterized by depressed mood, anhedonia, insomnia, weight loss or gain, agitation or psychomotor retardation, fatigue, feelings of worthlessness or excessive guilt, diminished concentration, and suicidal ideation/behavior ( Diagnostic and Statistical Manual of Mental Disorders , fourth edition, text revision [ DSM-IV-TR ]). 1 MDD is one of the leading causes of disability in the world, affecting approximately 14.8 million American adults with a lifetime prevalence rate of 19.2%. 2

OBJECTIVE Deep brain stimulation (DBS) is a reversible, nonlesion-based treatment for patients with intractable obsessive-compulsive disorder (OCD). The first studies on DBS for OCD stimulating the ventral capsule/ventral striatum (VC/VS) yielded encouraging results for this neuroanatomical site's therapeutic efficacy. This investigation was conducted to better understand which regions of the cortico-striatal-thalamic-cortical network were acutely affected by VC/VS DBS for OCD. Furthermore, the objective was to identify which brain regions demonstrated changes in perfusion, as stimulation was applied across a dorsoventral lead axis that corresponded to different anatomical locations in the VC/VS. METHODS Six patients receiving VC/VS DBS for OCD underwent oxygen-15 positron emission tomography (15O-PET) scanning. Monopolar DBS was delivered at each of the 4 different electrodes on the stimulating lead in the VC/VS. The data were analyzed using SPM5. Paired t-tests were run in SPSS to identify significant changes in regional cerebral blood flow (rCBF) between stimulation conditions. Pearson's r correlations were run between these significant changes in rCBF and changes in OCD and depressive symptom severity. RESULTS Perfusion in the dorsal anterior cingulate cortex (dACC) significantly increased when monopolar DBS was turned on at the most ventral DBS contact, and this increase in dACC activity was correlated with reductions in depressive symptom severity (r(5) = −0.994, p = 0.001). Perfusion in the thalamus, striatum, and globus pallidus significantly increased when DBS was turned on at the most dorsal contact. CONCLUSIONS DBS of the VC/VS appears to modulate activity in the regions implicated in the pathophysiology of OCD. Different regions in the cortico-striatal-thalamic-cortical circuit showed increased perfusion based on whether the stimulation was more ventral or dorsal along the lead axis in the VC/VS. Evidence was found that DBS at the most ventral site was associated with clinical changes in depressive symptom severity, but not OCD symptom severity.

Background Stress is widely known to alter behavioral responses to rewards and punishments. It is believed that stress may precipitate these changes through modulation of corticostriatal circuitry involved in reinforcement learning and motivation, although the intervening mechanisms remain unclear. One candidate is inflammation, which can rapidly increase following stress and can disrupt dopamine-dependent reward pathways. Methods Here, in a sample of 88 healthy female participants, we first assessed the effect of an acute laboratory stress paradigm on levels of plasma interleukin-6 (IL-6), a cytokine known to be both responsive to stress and elevated in depression. In a second laboratory session, we examined the effects of a second laboratory stress paradigm on reward prediction error (RPE) signaling in the ventral striatum. Results We show that individual differences in stress-induced increases in IL-6 (session 1) were associated with decreased ventral striatal RPE signaling during reinforcement learning (session 2), though there was no main effect of stress on RPE. Furthermore, changes in IL-6 following stress predicted intraindividual variability in perceived stress during a 4-month follow-up period. Conclusions Taken together, these data identify a novel link between IL-6 and striatal RPEs during reinforcement learning in the context of acute psychological stress, as well as future appraisal of stressful life events.

Based on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. By removing reactive species, MnPs affect redox-based cellular transcriptional activity and consequently secondary oxidative stress, and in turn inflammatory processes. The equal ability to reduce and oxidize superoxide during the dismutation process and recently accumulated results suggest that pro-oxidative actions of MnPs may also contribute to their therapeutic effects. All our data identify the superoxide dismutase-like activity, estimated by log kcat(O2–), as a good measure for the therapeutic efficacy of MnPs. Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP5+, MnTDE-2-ImP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are under preclinical and clinical development.

Obesity is associated with hyperactivation of the reward system for high-calorie (HC) versus low-calorie (LC) food cues, which encourages unhealthy food selection and overeating. However, the extent to which this hyperactivation can be reversed is uncertain, and to date there has been no demonstration of changes by behavioral intervention. We used functional magnetic resonance imaging to measure changes in activation of the striatum for food images at baseline and 6 months in a pilot study of 13 overweight or obese adults randomized to a control group or a novel weight-loss intervention. Compared to controls, intervention participants achieved significant weight loss (−6.3±1.0 kg versus +2.1±1.1 kg, P

Decision making in both animals and humans is influenced by the anticipation of reward and/or punishment. Little is known about how reward and punishment interact in the context of decision making. The Avoidance–Reward Conflict (ARC) Task is a new paradigm that varies the degree of reward and the probability of punishment in a single paradigm that can be used in both non-human primates (NHPs) and humans. This study examined the behavioral pattern in the ARC task in both NHPs and humans. Two adult male NHPs (macaca mulatta) and 20 healthy human volunteers (12 females) participated in the ARC task. NHPs and humans perform similarly on the ARC task. With a high probability of punishment (an aversive air puff to the eye), both NHPs and humans are more likely to forgo reward if it is small or medium magnitude than when it is large. Both NHPs and humans perform similarly on the same behavioral task suggesting the reliability of animal models in predicting human behavior.

Over a century ago, hypertrophy of astrocytes was noted as a pathology of multiple sclerosis (MS) and was hypothesized to play an important role in this disease, yet the contribution of astrocytes has been largely underemphasized in the pathophysiology of CNS demyelination. Astrocytes perform many homeostatic functions within the developing and adult CNS, including enhancing formation and maintenance of the blood–brain barrier, moderating neuronal connections through the tripartite synapse, and perhaps evenoffering intercellular communication independently of neurons. Although there is a significant body of literature characterizing different types of MS lesions, the inflammatory demyelination in an active MS lesion is accompanied by the presence of macrophages, lymphocytes, and large reactive astrocytes. The astrocyte has long been viewed as a cell that promotes inflammation and demyelination, while also forming the glial scar, thus hindering remyelination and axon growth. Renewed interest in the astrocyte has been brought about by recent studies demonstrating that astrocytes can also function as cellular mediators of CNS myelination by promoting oligodendrocyte progenitor migration, proliferation, and differentiation. Thus, refining our knowledge of astrocytic functions in the regulation of CNS myelination may help us to better understand why remyelination fails in MS. © 2010 Wiley-Liss, Inc.

Background: This study sought to investigate the efficacy of duloxetine for the treatment of obsessive-compulsive disorder (DSM-IV). Methods: Twenty individuals were enrolled in a 17-week, open-label trial of duloxetine at Massachusetts General Hospital. Data were collected between March 2007 and September 2012. Study measures assessing obsessive-compulsive disorder symptoms, quality of life, depression, and anxiety were administered at baseline and weeks 1, 5, 9, 13, and 17. The primary outcome measures were the Yale-Brown Obsessive Compulsive Scale and Clinical Global Improvement scale. Results: For the 12 study completers, pre- and posttreatment analyses revealed significant improvements (P < .05) on clinicianand self-rated measures of obsessive-compulsive disorder symptoms and quality of life. Among the 12 completers, more than one-half (n = 7) satisfied full medication response criteria. Intention-to-treat analyses (n = 20) showed similar improvements (P < .05) on primary and secondary study outcome measures. Conclusion: The results of this study suggest that duloxetine may provide a significant reduction in symptoms for patients with obsessive-compulsive disorder. ClinicalTrials.gov NCT00464698; http://clinicaltrials.gov/ct2/show/NCT00464698?term=NCT00464698&rank=1.