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.

Prevalent and sex-biased breathing patterns modify functional connectivity MRI in young adults.

Resting state functional connectivity magnetic resonance imaging (fMRI) is a tool for investigating human brain organization. Here we identify, visually and algorithmically, two prevalent influences on fMRI signals during 440 h of resting state scans in 440 healthy young adults, both caused by deviations from normal breathing which we term deep breaths and bursts. The two respiratory patterns have distinct influences on fMRI signals and signal covariance, distinct timescales, distinct cardiovascular correlates, and distinct tendencies to manifest by sex. Deep breaths are not sex-biased. Bursts, which are serial taperings of respiratory depth typically spanning minutes at a time, are more common in males. Bursts share features of chemoreflex-driven clinical breathing patterns that also occur primarily in males, with notable neurological, psychiatric, medical, and lifespan associations. These results identify common breathing patterns in healthy young adults with distinct influences on functional connectivity and an ability to differentially influence resting state fMRI studies.

Characteristics of respiratory measures in young adults scanned at rest, including systematic changes and "missed" deep breaths.

Breathing rate and depth influence the concentration of carbon dioxide in the blood, altering cerebral blood flow and thus functional magnetic resonance imaging (fMRI) signals. Such respiratory fluctuations can have substantial influence in studies of fMRI signal covariance in subjects at rest, the so-called "resting state functional connectivity" technique. If respiration is monitored during fMRI scanning, it is typically done using a belt about the subject's abdomen to record abdominal circumference. Several measures have been derived from these belt records, including the windowed envelope of the waveform (ENV), the windowed variance in the waveform (respiration variation, RV), and a measure of the amplitude of each breath divided by the cycle time of the breath (respiration volume per time, RVT). Any attempt to gauge respiratory contributions to fMRI signals requires a respiratory measure, but little is known about how these measures compare to each other, or how they perform beyond the small studies in which they were initially proposed. Here, we examine the properties of these measures in hundreds of healthy young adults scanned for an hour each at rest, a subset of the Human Connectome Project chosen for having high-quality physiological records. We find: 1) ENV, RV, and RVT are all correlated, and ENV and RV are more highly correlated to each other than to RVT; 2) respiratory events like deep breaths exhibit characteristic heart rate elevations, fMRI signal changes, head motions, and image quality abnormalities time-locked to large deflections in the belt traces; 3) all measures can "miss" deep breaths; 4) RVT "misses" deep breaths more than ENV or RV; 5) all respiratory measures change systematically over the course of a 14.4-min scan. We discuss the implications of these findings for the literature and ways to move forward in modeling respiratory influences on fMRI scans.

Distinctions among real and apparent respiratory motions in human fMRI data.

Head motion estimates in functional magnetic resonance imaging (fMRI) scans appear qualitatively different with sub-second image sampling rates compared to the multi-second sampling rates common in the past. Whereas formerly the head appeared still for much of a scan with brief excursions from baseline, the head now appears to be in constant motion, and motion estimates often seem to divulge little information about what is happening in a scan. This constant motion has been attributed to respiratory oscillations that do not alias at faster sampling rates, and investigators are divided on the extent to which such motion is "real" motion or only "apparent" pseudomotion. Some investigators have abandoned the use of motion estimates entirely due to these considerations. Here we investigate the properties of motion in several fMRI datasets sampled at rates between 720 and 1160 ms, and describe 5 distinct kinds of respiratory motion: 1) constant real respiratory motion in the form of head nodding most evident in vertical position and pitch, which can be very large; 2) constant pseudomotion at the same respiratory rate as real motion, occurring only in the phase encode direction; 3) punctate real motions occurring at times of very deep breaths; 4) a low-frequency pseudomotion in only the phase encode direction at and after very deep breaths; 5) slow modulation of vertical and anterior-posterior head position by the respiratory envelope. We reformulate motion estimates in light of these considerations and obtain good concordance between motion estimates, physiologic records, image quality measures, and events evident in the fMRI signals. We demonstrate how variables describing respiration or body habitus separately scale with distinct kinds of head motion. We also note heritable aspects of respiration and motion.

Functional and Optogenetic Approaches to Discovering Stable Subtype-Specific Circuit Mechanisms in Depression.

BACKGROUND: Previously, we identified four depression subtypes defined by distinct functional connectivity alterations in depression-related brain networks, which in turn predicted clinical symptoms and treatment response. Optogenetic functional magnetic resonance imaging offers a promising approach for testing how dysfunction in specific circuits gives rise to subtype-specific, depression-related behaviors. However, this approach assumes that there are robust, reproducible correlations between functional connectivity and depressive symptoms-an assumption that was not extensively tested in previous work. METHODS: First, we comprehensively reevaluated the stability of canonical correlations between functional connectivity and symptoms (N = 220 subjects) using optimized approaches for large-scale statistical hypothesis testing, and we validated methods for improving estimation of latent variables driving brain-behavior correlations. Having confirmed this necessary condition, we reviewed recent advances in optogenetic functional magnetic resonance imaging and illustrated one approach to formulating hypotheses regarding latent subtype-specific circuit mechanisms and testing them in animal models. RESULTS: Correlations between connectivity features and clinical symptoms were robustly significant, and canonical correlation analysis solutions tested repeatedly on held-out data generalized. However, they were sensitive to data quality, preprocessing, and clinical heterogeneity, which can reduce effect sizes. Generalization could be markedly improved by adding L2 regularization, which decreased estimator variance, increased canonical correlations in left-out data, and stabilized feature selection. These improvements were useful for identifying candidate circuits for optogenetic interrogation in animal models. CONCLUSIONS: Multiview, latent-variable approaches such as canonical correlation analysis offer a conceptually useful framework for discovering stable patient subtypes by synthesizing multiple clinical and functional measures. Optogenetic functional magnetic resonance imaging holds promise for testing hypotheses regarding latent, subtype-specific mechanisms driving depressive symptoms and behaviors.

A double-blind pilot dosing study of low field magnetic stimulation (LFMS) for treatment-resistant depression (TRD).

BACKGROUND: Low field magnetic stimulation is a potentially rapid-acting treatment for depression with mood-enhancing effects in as little as one 20-min session. The most convincing data for LFMS has come from treating bipolar depression. We examined whether LFMS also has rapid mood-enhancing effects in treatment-resistant major depressive disorder, and whether these effects are dose-dependent. OBJECTIVE/HYPOTHESIS: We hypothesized that a single 20-min session of LFMS would reduce depressive symptom severity and that the magnitude of this change would be greater after three 20-min sessions than after a single 20-min session. METHODS: In a double-blind randomized controlled trial, 30 participants (age 21-65) with treatment-resistant depression were randomized to three 20-min active or sham LFMS treatments with 48 h between treatments. Response was assessed immediately following LFMS treatment using the 6-item Hamilton Depression Rating Scale (HAMD-6), the Positive and Negative Affect Scale (PANAS) and the Visual Analog Scale. RESULTS: Following the 3rd session of LFMS, the effect of LFMS on VAS and HAMD-6 was superior to sham (F (1, 24) = 7.45, p = 0.03, Bonferroni-Holm corrected; F (1, 22) = 6.92, p = 0.03, Bonferroni-Holm corrected, respectively). There were no differences between sham and LFMS following the initial or second session with the effect not becoming significant until after the third session. CONCLUSIONS: Three 20-min LFMS sessions were required for active LFMS to have a mood-enhancing effect for individuals with treatment-resistant depression. As this effect may be transient, future work should address dosing schedules of longer treatment courses as well as biomarker-based targeting of LFMS to optimize patient selection and treatment outcomes.

GABA-modulating bacteria of the human gut microbiota.

The gut microbiota affects many important host functions, including the immune response and the nervous system1. However, while substantial progress has been made in growing diverse microorganisms of the microbiota2, 23-65% of species residing in the human gut remain uncultured3,4, which is an obstacle for understanding their biological roles. A likely reason for this unculturability is the absence in artificial media of key growth factors that are provided by neighbouring bacteria in situ5,6. In the present study, we used co-culture to isolate KLE1738, which required the presence of Bacteroides fragilis to grow. Bioassay-driven purification of B. fragilis supernatant led to the isolation of the growth factor, which, surprisingly, is the major inhibitory neurotransmitter GABA (γ-aminobutyric acid). GABA was the only tested nutrient that supported the growth of KLE1738, and a genome analysis supported a GABA-dependent metabolism mechanism. Using growth of KLE1738 as an indicator, we isolated a variety of GABA-producing bacteria, and found that Bacteroides ssp. produced large quantities of GABA. Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA. A transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides, Parabacteroides and Escherichia species. By coupling 16S ribosmal RNA sequencing with functional magentic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression.

Rostral anterior cingulate cortex is a structural correlate of repetitive TMS treatment response in depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for medication-refractory major depression, yet the mechanisms of action for this intervention are poorly understood. Here we investigate cerebral cortex thickness as a possible biomarker of rTMS treatment response. METHODS: Longitudinal change in cortical thickness is evaluated relative to clinical outcomes across 48 participants in 2 cohorts undergoing left dorsolateral prefrontal cortex rTMS as a treatment for depression. RESULTS: Our results reveal changes in thickness in a region of the left rostral anterior cingulate cortex that correlate with clinical response, with this region becoming thicker in patients who respond favorably to rTMS and thinner in patients with a less favorable response. Moreover, the baseline cortical thickness in this region correlates with rTMS treatment response - those patients with thinner cortex before treatment tended to have the most clinical improvement. CONCLUSIONS: This study is the first analysis of longitudinal cortical thickness change with rTMS as a treatment for depression with similar results across two cohorts. These results support further investigation into the use of structural MRI as a possible biomarker of rTMS treatment response.

The effect of a therapeutic lithium level on a stroke-related cerebellar tremor.

Lithium is a mood stabiliser used in the treatment of acute mania, bipolar disorder and as augmentation for unipolar major depression. Tremor is a common adverse effect associated with lithium at both therapeutic and toxic serum levels. We present a case of dose-dependent changes in the quality and intensity of a stroke-related, chronic cerebellar tremor with lithium treatment at serum levels within the therapeutic range. On admission, the patient in this case had a baseline fine, postural tremor, which increased in frequency and evolved to include myoclonic jerks once lithium therapy was initiated. Although the patient's serum lithium level was never in the toxic range, his tremor returned to baseline on reduction of his serum lithium level. This case highlights that a pre-existing, baseline tremor may lower the threshold for developing myoclonus. It also suggests that caution may be warranted with lithium therapy in the setting of known cerebellar disease.

Age-Related Repetitive Transcranial Magnetic Stimulation Effects on Executive Function in Depression: A Systematic Review.

OBJECTIVE: The aims of the current review were to: 1) examine whether the rTMS effects on executive function increase as age advances; 2) to examine the potential of rTMS to remediate executive function in older depressed patients; and 3) to assess the relationship between the executive function and mood benefits from rTMS in depression. METHODS: Randomized or matched-groups, blind, sham-controlled studies (12 studies, 347 participants) on excitatory rTMS applied to left DLPFC in depression were reviewed. RESULTS: A series of meta-regressions found no evidence of greater rTMS effects on executive functions as age advances. Similarly, meta-analyses showed no significant rTMS effects on executive functions in older depressed individuals. However, meta-regression analyses showed that the size of the executive function benefits from rTMS in depression are positively related to the effect size of mood symptom reduction. Despite its correlational nature, this finding is consistent with the idea that improvement in executive function may play a critical role in depression recovery. CONCLUSIONS: The authors consider these findings preliminary because of the modest number of available studies. Based on a qualitative review, the authors describe methodologic modifications that may increase rTMS efficacy for both executive functions and mood in late-life depression.

Functional connectivity of the left DLPFC to striatum predicts treatment response of depression to TMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is a non-invasive, safe, and efficacious treatment for depression. TMS has been shown to normalize abnormal functional connectivity of cortico-cortical circuits in depression and baseline functional connectivity of these circuits predicts treatment response. Less is known about the relationship between functional connectivity of frontostriatal circuits and treatment response. OBJECTIVE/HYPOTHESIS: We investigated whether baseline functional connectivity of distinct frontostriatal circuits predicted response to TMS. METHODS: Resting-state fMRI (rsfMRI) was acquired in 27 currently depressed subjects with treatment resistant depression and 27 healthy controls. Depressed subjects were treated with 5 weeks of daily TMS over the left dorsolateral prefrontal cortex (DLPFC). The functional connectivity between limbic, executive, rostral motor, and caudal motor regions of frontal cortex and their corresponding striatal targets were determined at baseline using an existing atlas based on diffusion tensor imaging. TMS treatment response was measured by percent reduction in the 24-item Hamilton Depression Rating Scale (HAMD24). In an exploratory analysis, correlations were determined between baseline functional connectivity and TMS treatment response. RESULTS: Seven cortical clusters belonging to the executive and rostral motor frontostriatal projections had reduced functional connectivity in depression compared to healthy controls. No frontostriatal projections showed increased functional connectivity in depression (voxel-wise p < 0.01, family-wise α < 0.01). Only baseline functional connectivity between the left DLPFC and the striatum predicted TMS response. Higher baseline functional connectivity correlated with greater reductions in HAMD24 (Pearson's R = 0.58, p = 0.002). CONCLUSION(S): In an exploratory analysis, higher functional connectivity between the left DLPFC and striatum predicted better treatment response. Our findings suggest that the antidepressant mechanism of action of TMS may require connectivity from cortex proximal to the stimulation site to the striatum.

Network-Guided Transcranial Magnetic Stimulation for Depression.

PURPOSE OF REVIEW: First, we will identify candidate predictive biomarkers of antidepressant response of TMS based on the neuroimaging literature. Next, we will review the effects of TMS on networks involved in depression. Finally, we will discuss ways in which our current understanding of network engagement by TMS may be used to optimize its antidepressant effect. RECENT FINDINGS: The past few years has seen significant interest in the antidepressant mechanisms of TMS. Studies using functional neuroimaging and neurochemical imaging have demonstrated engagement of networks known to be important in depression. Current evidence supports a model whereby TMS normalizes network function gradually over the course of several treatments. This may, in turn, mediate its antidepressant effect. SUMMARY: One strategy to optimize the antidepressant effect of TMS is to more precisely target networks relevant in depression. We propose methods to achieve this using functional and neurochemical imaging.

Resting-state connectivity biomarkers define neurophysiological subtypes of depression.

Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

A naturalistic, multi-site study of repetitive transcranial magnetic stimulation therapy for depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) was approved in 2008 in the United States, and there are relatively few studies describing its use in regular clinical practice since approval. METHODS: From April 2011 to October 2014, ten sites within the National Network of Depression Centers (NNDC) provided data on 62 evaluable patients with a depressive episode. Treatment was determined naturalistically. Response was assessed by the Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR) as the primary outcome, and the Patient Health Questionnaire-9 (PHQ-9) and the clinician-rated Clinical Global Impression (CGI) as secondary depression measures. RESULTS: Enrolled patients exhibited significant treatment resistance, with 70.2% reporting more than 4 prior depressive episodes. Most patients received treatment with standard parameters (10Hz over the left dorsolateral prefrontal cortex), although 22.6% of the patients received 1 or 5Hz stimulation at some point. Over 6 weeks of treatment, response and remission rates were 29.4% and 5.9%, respectively, for the QIDS-SR; 39.2% and 15.7%, respectively, for the PHQ-9; and 50.9% and 17.9%, respectively, for the CGI. Moderator analyses revealed no effect of prior depressive episodes, history of ECT or gender, although early life stress predicted a better response to rTMS therapy. LIMITATIONS: The study was an open-label, registry trial, with relatively coarse clinical data, reflecting practice only in academic, depression-specialty centers. Because of the relatively small size and heterogeneity of the sample, type 2 errors are possible and positive findings are in need of replication. CONCLUSION: rTMS demonstrates effectiveness in clinical practice within the NNDC, although remission rates appear slightly lower in comparison with other recent naturalistic studies.

Oxcarbazepine-induced liver injury after sensitization by valproic acid: a case report.

OBJECTIVE: The aim of the present case report is to describe a potential interaction between valproic acid and oxcarbazepine that resulted in hepatic injury. METHODS: We report the case of a 46-year-old man with schizoaffective disorder who was cross-titrated from valproic acid to oxcarbazepine because of liver injury. RESULTS: Initiation of oxcarbazepine four days after stopping valproic acid produced a significant elevation in liver enzymes that normalized with oxcarbazepine discontinuation and did not reappear with its reintroduction five days later. CONCLUSIONS: Our findings suggest that a longer washout period or another agent should be considered when transitioning from valproic acid to oxcarbazepine.

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy.

BACKGROUND: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy ((1)H MRS). METHODS: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with (1)H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). RESULTS: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC increased 13.8% (p = 0.013) in all depressed individuals. There were no significant effects of rTMS on Glx/W. GABA/W and Glx/W were highly correlated in severely depressed patients at baseline but not after TMS. LIMITATIONS: The primary study limitations are the open-label design and the inclusion of participants currently taking stable regimens of antidepressant medications. CONCLUSION: These results implicate GABAergic and glutamatergic systems in the mechanism of action of rTMS for major depression, warranting further investigation in larger samples.

Default mode network mechanisms of transcranial magnetic stimulation in depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks-the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)-are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response. METHODS: We used resting state functional magnetic resonance imaging to measure functional connectivity within and between the DMN and CEN in 17 depressed patients, before and after a 5-week course of TMS. Motivated by prior reports, we focused on connectivity seeded from the DLPFC and the subgenual cingulate, a key region closely aligned with the DMN in depression. Connectivity was also compared with a cohort of 35 healthy control subjects. RESULTS: Before treatment, functional connectivity in depressed patients was abnormally elevated within the DMN and diminished within the CEN, and connectivity between these two networks was altered. Transcranial magnetic stimulation normalized depression-related subgenual hyperconnectivity in the DMN but did not alter connectivity in the CEN. Transcranial magnetic stimulation also induced anticorrelated connectivity between the DLPFC and medial prefrontal DMN nodes. Baseline subgenual connectivity predicted subsequent clinical improvement. CONCLUSIONS: Transcranial magnetic stimulation selectively modulates functional connectivity both within and between the CEN and DMN, and modulation of subgenual cingulate connectivity may play an important mechanistic role in alleviating depression. The results also highlight potential neuroimaging biomarkers for predicting treatment response.

Prefrontal cortical blood flow predicts response of depression to rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for resistant major depressive disorder. The response rate of rTMS for depression is modest, motivating the search for biomarkers predictive of treatment response. METHODS: Thirteen patients (mean age 45 years, three males) with current major depression resistant to at least one antidepressant trial in the current episode were treated with a 25 day course of rTMS over the left dorsolateral prefrontal cortex (DLPFC). Resting state cerebral perfusion was measured prior to the first day of treatment and after the final day of treatment. Treatment response was measured using the Hamilton Depression Rating Scale-24 Item (Ham-D). Baseline cerebral perfusion was compared in responders to non-responders. In addition, post-treatment cerebral perfusion was compared to pre-treatment in responders as well as in non-responders. RESULTS: Six individuals responded to rTMS. Responders had greater resting state blood flow in the left DLPFC (the target site) at baseline compared to non-responders. Non-responders showed greater baseline activity in the left medial frontal cortex. Neither group exhibited changes during treatment, nor did the combined group. LIMITATIONS: This study suffers from low sample size and resulting small responder and non-responder subgroups. The sample was not balanced to gender. A normal control group was not included. CONCLUSIONS: We believe this is the first study to compare pre-treatment brain perfusion patterns of depressed individuals who responded to rTMS to those who did not. Our results suggest stronger left DLPFC perfusion in responders and stronger medial prefrontal perfusion in non-responders both at baseline and post-treatment. These results await confirmation in a larger, prospective, placebo-controlled study.

Identification of a circuit-based endophenotype for familial depression.

Frontal and parietal lesions may cause depression, and cortical thinning of the right frontal and parietal lobes has been shown to be a marker of risk for familial major depression. We studied biological offspring within a three-generation cohort, in which risk was defined by the depression status of the first generation, to identify regional volume differences associated with risk for depression throughout the cerebrum. We found reduced frontal and parietal white matter volumes in the high-risk group, including in persons without any personal history of depression, suggesting that hypoplasia of frontal and parietal white matter is an endophenotype for familial depression. In addition, white matter volumes in these regions correlated with current severity of symptoms of depression, inattention, and impulsivity. White matter volumes also correlated strongly with the degree of thinning in the right parietal cortex. These findings support a model of pathogenesis in which hypoplasia within a neural network for attention and emotional processing predisposes to depression.