National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Neuromodulation Strategies for the Treatment of Depression.

For many decades, psychiatric treatment has been primarily guided by two major paradigms of psychopathology: a neurochemical paradigm leading to the development of medications and a psychological paradigm resulting in the development of psychotherapies. A third paradigm positing that psychiatric dysfunction results from abnormal communication within a network of brain regions that regulate mood, thought, and behavior has gained increased attention over the past several years and underlies the development of multiple neuromodulation and neurostimulation therapies. This neural circuit paradigm is not new. In the late 19th and early 20th centuries, it was a common way of understanding psychiatric illness and led to several of our earliest somatic therapies. However, with the rise of effective medications and evidence-based psychotherapies, this paradigm went mostly dormant. Its recent reemergence resulted from a growing recognition that medications and psychotherapy leave many patients inadequately treated, along with technological advances that have revolutionized our ability to understand and modulate the neural circuitry involved in psychiatric disorders. In this overview, the authors review the history and current state of neuromodulation for psychiatric illness and specifically focus on these approaches as a treatment for depression, as this has been the primary indication for these interventions over time.

Depression Comorbid With Stroke, Traumatic Brain Injury, Parkinson's Disease, and Multiple Sclerosis: Diagnosis and Treatment.

Depression is common among patients with neurologic disorders, and it has long been considered more difficult to treat than depression in the general population. In this review, the authors consider challenges in the diagnosis and treatment of depression among patients with stroke, traumatic brain injury, Parkinson's disease, and multiple sclerosis. For each disorder, the authors discuss the epidemiology and time course of depression as well as review the physiologic and psychological etiologies of depression. In addition, for each disorder, they review screening tools and diagnostic considerations, including differential diagnosis; discuss etiological factors, both neurobiological and psychological; and assess evidence for various depression treatments, including pharmacologic, psychosocial, and neuromodulatory therapies. The evidence suggests that depression is common among patients with neurologic disorders and that it is crucial for general psychiatrists to provide treatment for this population.

Functional network connectivity in early-stage schizophrenia.

Schizophrenia is a disorder of altered neural connections resulting in impaired information integration. Whole brain assessment of within- and between-network connections may determine how information processing is disrupted in schizophrenia. Patients with early-stage schizophrenia (n = 56) and a matched control sample (n = 32) underwent resting-state fMRI scans. Gray matter regions were organized into nine distinct functional networks. Functional connectivity was calculated between 278 gray matter regions for each subject. Network connectivity properties were defined by the mean and variance of correlations of all regions. Whole-brain network measures of global efficiency (reflecting overall interconnectedness) and locations of hubs (key regions for communication) were also determined. The control sample had greater connectivity between the following network pairs: somatomotor-limbic, somatomotor-default mode, dorsal attention-default mode, ventral attention-limbic, and ventral attention-default mode. The patient sample had greater variance in interactions between ventral attention network and other functional networks. Illness duration was associated with overall increases in the variability of network connections. The control group had higher global efficiency and more hubs in the cerebellum network, while patient group hubs were more common in visual, frontoparietal, or subcortical networks. Thus, reduced functional connectivity in patients was largely present between distinct networks, rather than within-networks. The implications of these findings for the pathophysiology of schizophrenia are discussed.

Altered cerebral blood flow one month after systemic chemotherapy for breast cancer: a prospective study using pulsed arterial spin labeling MRI perfusion.

Cerebral structural and functional alterations have been reported after chemotherapy for non-CNS cancers, yet the causative mechanism behind these changes remains unclear. This study employed a novel, non-invasive, MRI-based neuroimaging measure to provide the first direct longitudinal measurement of resting cerebral perfusion in breast cancer patients, which was tested for association with changes in cognitive function and gray matter density. Perfusion was measured using pulsed arterial spin labeling MRI in women with breast cancer treated with (N = 27) or without (N = 26) chemotherapy and matched healthy controls (N = 26) after surgery before other treatments (baseline), and one month after chemotherapy completion or yoked intervals. Voxel-based analysis was employed to assess perfusion in gray matter; changes were examined in relation to overall neuropsychological test performance and frontal gray matter density changes measured by structural MRI. Baseline perfusion was not significantly different across groups. Unlike control groups, chemotherapy-treated patients demonstrated significantly increased perfusion post-treatment relative to baseline, which was statistically significant relative to controls in the right precentral gyrus. This perfusion increase was negatively correlated with baseline overall neuropsychological performance, but was not associated with frontal gray matter density reduction. However, decreased frontal gray matter density was associated with decreased perfusion in bilateral frontal and parietal lobes in the chemotherapy-treated group. These findings indicate that chemotherapy is associated with alterations in cerebral perfusion which are both related to and independent of gray matter changes. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. Additionally, lower baseline cognitive function may be a risk factor for treatment-associated perfusion dysregulation. Future research is needed to clarify these mechanisms, identify individual differences in susceptibility to treatment-associated changes, and further examine perfusion change over time in survivors.

Chemotherapy-induced amenorrhea: a prospective study of brain activation changes and neurocognitive correlates.

Chemotherapy-induced amenorrhea (CIA) often occurs in pre- and peri-menopausal BC patients, and while cancer/chemotherapy and abrupt estrogen loss have separately been shown to affect cognition and brain function, studies of the cognitive effects of CIA are equivocal, and its effects on brain function are unknown. Functional MRI (fMRI) during a working memory task was used to prospectively assess the pattern of brain activation and deactivation prior to and 1 month after chemotherapy in BC patients who experienced CIA (n = 9), post-menopausal BC patients undergoing chemotherapy (n = 9), and pre- and post-menopausal healthy controls (n = 6 each). Neurocognitive testing was also performed at both time points. Repeated measures general linear models were used to assess statistical significance, and age was a covariate in all analyses. We observed a group-by-time interaction in the combined magnitudes of brain activation and deactivation (p = 0.006): the CIA group increased in magnitude from baseline to post-treatment while other groups maintained similar levels over time. Further, the change in brain activity magnitude in CIA was strongly correlated with change in processing speed neurocognitive testing score (r = 0.837 p = 0.005), suggesting this increase in brain activity reflects effective cognitive compensation. Our results demonstrate prospectively that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Cognitive correlates add to the potential clinical significance of these findings. These findings have implications for risk appraisal and development of prevention or treatment strategies for cognitive changes in CIA.

Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage.

Neuroimaging studies have begun to uncover the neural substrates of cancer and treatment-related cognitive dysfunction, but the time course of these changes in the years following chemotherapy is unclear. This study analyzed multimodality 3T MRI scans to examine the structural and functional effects of chemotherapy and post-chemotherapy interval (PCI) in a cohort of breast cancer survivors (BCS; n = 24; PCI mean 6, range 3-10 y) relative to age- and education-matched healthy controls (HC; n = 23). Assessments included voxel-based morphometry for gray matter density (GMD) and fMRI for activation profile during a 3-back working memory task. The relationships between brain regions associated with PCI and neuropsychological performance, self-reported cognition, and oxidative and direct DNA damage as measured in peripheral lymphocytes were assessed in secondary analyses. PCI was positively associated with GMD and activation on fMRI in the right anterior frontal region (Brodmann Areas 9 and 10) independent of participant age. GMD in this region was also positively correlated with global neuropsychological function. Memory dysfunction, cognitive complaints, and oxidative DNA damages were increased in BCS compared with HC. Imaging results indicated lower fMRI activation in several regions in the BCS group. BCS also had lower GMD than HC in several regions, and in these regions, GMD was inversely related to oxidative DNA damage and learning and memory neuropsychological domain scores. This is the first study to show structural and functional effects of PCI and to relate oxidative DNA damage to brain alterations in BCS. The relationship between neuroimaging and cognitive function indicates the potential clinical relevance of these findings. The relationship with oxidative DNA damage provides a mechanistic clue warranting further investigation.

Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: a replication and extension study.

Cognitive changes related to cancer and its treatment have been intensely studied, and neuroimaging has begun to demonstrate brain correlates. In the first prospective longitudinal neuroimaging study of breast cancer (BC) patients we recently reported decreased gray matter density one month after chemotherapy completion, particularly in frontal regions. These findings helped confirm a neural basis for previously reported cognitive symptoms, which most commonly involve executive and memory processes in which the frontal lobes are a critical component of underlying neural circuitry. Here we present data from an independent, larger, more demographically diverse cohort that is more generalizable to the BC population. BC patients treated with (N=27) and without (N=28) chemotherapy and matched healthy controls (N=24) were scanned at baseline (prior to systemic treatment) and one month following chemotherapy completion (or yoked intervals for non-chemotherapy and control groups) and APOE-genotyped. Voxel-based morphometry (VBM) showed decreased frontal gray matter density after chemotherapy, as observed in the prior cohort, which was accompanied by self-reported difficulties in executive functioning. Gray matter and executive symptom changes were not related to APOE ε4 status, though a somewhat greater percentage of BC patients who received chemotherapy were ε4 allele carriers than patients not treated with chemotherapy or healthy controls. These findings provide confirmatory evidence of frontal morphometric changes that may be a pathophysiological basis for cancer and treatment-related cognitive dysfunction. Further research into individual risk factors for such changes will be critical for development of treatment and prevention strategies.

Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study.

PURPOSE: To prospectively examine alterations in working memory (WM) -associated brain activation related to breast cancer and treatment by using functional magnetic resonance imaging. PATIENTS AND METHODS: Patients treated with chemotherapy (CTx+; n = 16) or without chemotherapy (CTx-; n = 12) and healthy controls (n = 15) were scanned during an n-back task at baseline (after surgery but before radiation, chemotherapy, and/or antiestrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1), or at yoked intervals for CTx- and controls. SPM5 was used for all image analyses, which included cross-sectional between-group and group-by-time interaction and longitudinal within-group analyses, all using a statistical threshold of 0.001. RESULTS: At baseline, patients with cancer showed increased bifrontal and decreased left parietal activation compared with controls. At M1, both cancer groups showed decreased frontal hyperactivation compared with controls, with increased hyperactivation at Y1. These cross-sectional findings were confirmed by group-by-time interaction analyses, which showed frontal activation decreases from baseline to M1 in patients compared with controls. Within-group analyses showed different patterns of longitudinal activation change by treatment group (CTx+ or CTx-), with prominent alterations in the frontal lobes bilaterally. CONCLUSION: Significant frontal lobe hyperactivation to support WM was found in patients with breast cancer. Superimposed on this background, patients showed decreased frontal activation at M1, with partial return to the previously abnormal baseline at Y1. These functional changes correspond to frontal lobe regions where we previously reported structural changes in this cohort and provide prospective, longitudinal data that further elucidate mechanisms underlying cognitive effects related to breast cancer and its treatment.

Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study.

Brain gray matter alterations have been reported in cross-sectional magnetic resonance imaging (MRI) studies of breast cancer patients after cancer treatment. Here we report the first prospective MRI study of women undergoing treatment for breast cancer, with or without chemotherapy, as well as healthy controls. We hypothesized that chemotherapy-associated changes in gray matter density would be detectable 1 month after treatment, with partial recovery 1 year later. Participants included breast cancer patients treated with (CTx+, N = 17) or without (CTx-, N = 12) chemotherapy and matched healthy controls (N = 18). MRI scans were acquired at baseline (after surgery but before radiation, chemotherapy, and/or anti-estrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1). Voxel-based morphometry (VBM) was used to evaluate gray matter density differences between groups and over time. There were no between-group gray matter differences at baseline. Group-by-time interactions showed declines from baseline to M1 in both cancer groups relative to controls. Within-group analyses indicated that at M1 relative to baseline the CTx+ group had decreased gray matter density in bilateral frontal, temporal, and cerebellar regions and right thalamus. Recovery was seen at Y1 in some regions, although persistent decreases were also apparent. No significant within-group changes were found in the CTx- or control groups. Findings were not attributable to recency of cancer surgery, disease stage, psychiatric symptoms, psychotropic medication use, or hormonal treatment status. This study is the first to use a prospective, longitudinal approach to document decreased brain gray matter density shortly after breast cancer chemotherapy and its course of recovery over time. These gray matter alterations appear primarily related to the effects of chemotherapy, rather than solely reflecting host factors, the cancer disease process, or effects of other cancer treatments.

Cortical-striatal integration of cocaine history and prefrontal dysfunction in animal modeling of dual diagnosis.

BACKGROUND: High rates of substance disorders in schizophrenia and other mental illnesses may reflect biological vulnerabilities to the addiction process. Interactions between addictive drug effects and mental illness involving circuits that generate motivated behavior may underpin this vulnerability. METHODS: We examined separate and combined effects of neonatal ventral hippocampal lesions (NVHLs)-a neurodevelopmental model of schizophrenia (vs. SHAM-operated control animals)--and a behaviorally sensitizing cocaine history (15 mg/kg/day x 5 days vs. saline injections) on acute cocaine-induced neural activation signaled by c-Fos expression. Stereological assessment of activation densities spanned six ventral to dorsal cortical-striatal compartments. RESULTS: Cortically, NVHLs showed hypoactivation and decreased volume of the ventral medial prefrontal cortex. In contrast, cocaine history was only expressed subcortically and as a hyperactivating effect in the dorsal striatum where significant NVHL-induced hyperactivation also emerged. Across all subjects and brain regions, only dorsal striatal activation was correlated with differences in sensitized locomotion. However, this activation was tightly correlated to a simple multiplicative function of ventral medial prefrontal hypoactivation and cocaine history-related increases in striatal activation. CONCLUSIONS: These findings suggest drug history and developmental temporal limbic abnormalities associated with prefrontal dysfunction produce compounding effects within cortical-striatal circuits as mechanistic basis for dual diagnosis.

Neonatal amygdala lesions: co-occurring impact on social/fear-related behavior and cocaine sensitization in adult rats.

Neurodevelopmental abnormalities of temporal-limbic structures may underlie both adult psychiatric syndromes and increased addiction vulnerability, leading to high frequencies of "dual diagnosis" disorders. Although the amygdala is implicated in various mental disorders and drug addiction, no studies have explored the impact of early developmental damage to the amygdala on phenotypes relating to mental illness and addictions as co-occurring processes. We tested rats with neonatal amygdala lesions (NAML) vs. SHAM-operated controls in a battery of tests--novel field activity, elevated plus maze (EPM), and social interaction (SI) at baseline and after odor and restraint stress--followed by measures of cocaine sensitization (15 mg/kg vs. saline x 5 days + challenge session 2 weeks later) and remeasurement of SI. NAMLs showed increased novelty-related locomotion, less fear responding in the EPM, and resistance to predator-odor- but not to restraint-induced suppression of SI. NAMLs also had elevated cocaine sensitization profiles, and cocaine history differentially affected subsequent SI in NAMLs compared with SHAMs. NAMLs may provide models for understanding a shared neurobiological basis for and complex interactions among psychiatric symptoms, drug exposure history, and addiction vulnerability.

Network modeling of adult neurogenesis: shifting rates of neuronal turnover optimally gears network learning according to novelty gradient.

Apoptotic and neurogenic events in the adult hippocampus are hypothesized to play a role in cognitive responses to new contexts. Corticosteroid-mediated stress responses and other neural processes invoked by substantially novel contextual changes may regulate these processes. Using elementary three-layer neural networks that learn by incremental synaptic plasticity, we explored whether the cognitive effects of differential regimens of neuronal turnover depend on the environmental context in terms of the degree of novelty in the new information to be learned. In "adult" networks that had achieved mature synaptic connectivity upon prior learning of the Roman alphabet, imposition of apoptosis/neurogenesis before learning increasingly novel information (alternate Roman < Russian < Hebrew) reveals optimality of informatic cost benefits when rates of turnover are geared in proportion to the degree of novelty. These findings predict that flexible control of rates of apoptosis-neurogenesis within plastic, mature neural systems optimizes learning attributes under varying degrees of contextual change, and that failures in this regulation may define a role for adult hippocampal neurogenesis in novelty- and stress-responsive psychiatric disorders.

Ethanol sensitization in a neurodevelopmental lesion model of schizophrenia in rats.

Substance use disorder comorbidity in schizophrenia may reflect dysfunctional cortical-striatal-limbic circuitry commonly involved in the addiction process and the pathogenesis of schizophrenia. Rats with neonatal ventral hippocampal lesions (NVHL) demonstrate post-adolescent onset of schizophrenia-like symptoms and increased addiction vulnerability in paradigms using cocaine in adulthood. Here, we investigated response profiles of young adult NVHL vs. SHAM rats to ethanol, an addictive drug with many psychopharmacological effects divergent from those of cocaine, in a locomotor sensitization paradigm. Over 15 days of daily injections of saline, low (0.15 g/kg) or high (1.0 g/kg) doses of ethanol, NVHL rats showed stimulatory effects at the low dose compared to saline and high-dose conditions, while SHAM rats showed expected patterns of dose-dependent suppression of locomotor activity. In a challenge session 2 weeks later in which a moderate dose (0.25 g/kg) of ethanol was given to all subjects, NVHL rats with history of prior ethanol exposure showed greater locomotor activity consistent with installment of alcohol-induced sensitization not present in SHAMs. These findings provide further evidence of enhanced short- and long-term responsivity to abused drugs in a neurodevelopmental model of schizophrenia, and may reflect potentiation of common mechanisms of addiction shared between pharmacologically diverse addictive drugs.