Jonathan Downar

A multimodal cortical network for the detection of changes in the sensory environment

Sensory stimuli undergoing sudden changes draw attention and preferentially enter our awareness. We used event-related functional magnetic-resonance imaging (fMRI) to identify brain regions responsive to changes in visual, auditory and tactile stimuli. Unimodally responsive areas included visual, auditory and somatosensory association cortex. Multimodally responsive areas comprised a right-lateralized network including the temporoparietal junction, inferior frontal gyrus, insula and left cingulate and supplementary motor areas. These results reveal a distributed, multimodal network for involuntary attention to events in the sensory environment. This network contains areas thought to underlie the P300 event-related potential and closely corresponds to the set of cortical regions damaged in patients with hemineglect syndromes.

Neural correlates of the prolonged salience of painful stimulation.

Pain is a unique class of sensory experience from the perspective of salience. Nonpainful somatosensory stimuli usually require behavioral relevance or voluntary attention to maintain salience. In contrast, painful stimuli tend to have sustained salience even without explicit behavioral relevance or voluntary attention. We have previously identified a frontal-parietal-cingulate network of regions responding transiently to nonpainful sensory events. This network is sensitive to the task relevance and novelty of sensory events and likely represents the salience of events in the sensory environment. Since pain can remain salient for a prolonged period, we hypothesized that this network should show transient responses to the onset or offset of a nonpainful stimulus, but sustained responses throughout the duration of a painful stimulus. To test this hypothesis, we used functional MRI to examine the response of these regions to sustained (60-s) periods of painful and nonpainful transcutaneous electrical nerve stimulation. As predicted, the temporoparietal, inferior frontal, and anterior cingulate cortex showed only transient responses to the onset or offset of nonpainful stimulation, but a sustained response throughout the duration of painful stimulation. These regions therefore show tonic responses to stimuli with tonic salience, supporting a general role for these areas in representing stimulus salience. The thalamus and putamen also responded tonically throughout painful but not nonpainful stimulation. Previous studies have implicated the basal ganglia in supporting voluntary sustained attention. Our findings suggest that the basal ganglia may play a more general role in supporting sustained salience, whether through voluntary or involuntary mechanisms.

Anhedonia and Reward-Circuit Connectivity Distinguish Nonresponders from Responders to Dorsomedial Prefrontal Repetitive Transcranial Magnetic Stimulation in Major Depression

BACKGROUND Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brains emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. METHODS Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. RESULTS Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. CONCLUSIONS The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.

Resting-State Cortico-Thalamic-Striatal Connectivity Predicts Response to Dorsomedial Prefrontal rTMS in Major Depressive Disorder

Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased subgenual cingulate cortex-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Interoception drives increased rational decision-making in meditators playing the ultimatum game

Human decision-making is often conceptualized as a competition between cognitive and emotional processes in the brain. Deviations from rational processes are believed to derive from inclusion of emotional factors in decision-making. Here, we investigate whether experienced Buddhist meditators are better equipped to regulate emotional processes compared with controls during economic decision-making in the Ultimatum Game. We show that meditators accept unfair offers on more than half of the trials, whereas controls only accept unfair offers on one-quarter of the trials. By applying fMRI we show that controls recruit the anterior insula during unfair offers. Such responses are powerful predictors of rejecting offers in social interaction. By contrast, meditators display attenuated activity in high-level emotional representations of the anterior insula and increased activity in the low-level interoceptive representations of the posterior insula. In addition we show that a subset of control participants who play rationally (i.e., accepts >85% unfair offers) recruits the dorsolateral prefrontal cortex presumably reflecting increased cognitive demands, whereas rational meditators by contrast display elevated activity in the somatosensory cortex and posterior superior temporal cortex. In summary, when assessing unfairness in the Ultimatum Game, meditators activate a different network of brain areas compared with controls enabling them to uncouple negative emotional reactions from their behavior. These findings highlight the clinically and socially important possibility that sustained training in mindfulness meditation may impact distinct domains of human decision-making.

New Targets for rTMS in Depression: A Review of Convergent Evidence

Although rTMS is moving steadily into the mainstream as a treatment for medically refractory depression, its efficacy continues to lag behind that of more invasive neuromodulation treatments such as ECT or DBS. Here we review evidence to suggest that a fruitful, but neglected, strategy for improving rTMS efficacy may be to explore alternatives to the conventional stimulation target in the dorsolateral prefrontal cortex (DLPFC). The convergent evidence of lesion, stimulation, connectivity, and correlative neuroimaging studies suggests that the DLPFC may have a relatively peripheral role in mood regulation, at least compared to several alternative areas within the prefrontal cortex. In particular, we consider the evidence base in support of four new potential targets for rTMS in depression: dorsomedial prefrontal cortex (DMPFC), frontopolar cortex (FPC), ventromedial prefrontal cortex (VMPFC), and ventrolateral prefrontal cortex (VLPFC). Each of these regions enjoys broader support, from a more diverse evidence base, than the DLPFC in terms of its role in emotion regulation in major depression. We discuss the relative merits of each of these novel targets, including potential obstacles to stimulation using currently available technologies, and potential strategies for overcoming these obstacles. It is hoped that this detailed review will spur a more vigorous exploration of new targets for rTMS in depression. The use of new targets may help to propel rTMS across the threshold of efficacy required of a first-line treatment, to assume a more widespread role in the treatment of depressed mood.

rTMS of the Dorsomedial Prefrontal Cortex for Major Depression: Safety, Tolerability, Effectiveness, and Outcome Predictors for 10 Hz Versus Intermittent Theta-burst Stimulation

BACKGROUND Conventional rTMS protocols for major depression commonly employ stimulation sessions lasting >30 min. However, recent studies have sought to improve costs, capacities, and outcomes by employing briefer protocols such as theta burst stimulation (iTBS). OBJECTIVE To compare safety, effectiveness, and outcome predictors for DMPFC-rTMS with 10 Hz (30 min) versus iTBS (6 min) protocols, in a large, naturalistic, retrospective case series. METHODS A chart review identified 185 patients with a medication-resistant major depressive episode who underwent 20-30 sessions of DMPFC-rTMS (10 Hz, n = 98; iTBS, n = 87) at a single Canadian clinic from 2011 to 2014. RESULTS Clinical characteristics of 10 Hz and iTBS patients did not differ prior to treatment, aside from significantly higher age in iTBS patients. A total 7912 runs of DMPFC-rTMS (10 Hz, 4274; iTBS, 3638) were administered, without any seizures or other serious adverse events, and no significant differences in rates of premature discontinuation between groups. Dichotomous outcomes did not differ significantly between groups (Response/remission rates: Beck Depression Inventory-II: 10 Hz, 40.6%/29.2%; iTBS, 43.0%/31.0%. 17-item Hamilton Rating Scale for Depression: 10 Hz, 50.6%/38.5%; iTBS, 48.5%/27.9%). On continuous outcomes, there was no significant difference between groups in pre-treatment or post-treatment scores, or percent improvement on either measure. Mixed-effects modeling revealed no significant group-by-time interaction on either measure. CONCLUSIONS Both 10 Hz and iTBS DMPFC-rTMS appear safe and tolerable at 120% resting motor threshold. The effectiveness of 6 min iTBS and 30 min 10 Hz protocols appears comparable. Randomized trials comparing 10 Hz to iTBS may be warranted.

Unanticipated Rapid Remission of Refractory Bulimia Nervosa, during High-Dose Repetitive Transcranial Magnetic Stimulation of the Dorsomedial Prefrontal Cortex: A Case Report.

A woman with severe, refractory bulimia nervosa (BN) underwent treatment for comorbid depression using repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (DMPFC) using a novel technique. Unexpectedly, she showed a rapid, dramatic remission from BN. For 5 months pre-treatment, she had reported two 5-h binge-purge episodes per day. After rTMS session 2 the episodes stopped entirely for 1 week; after session 10 there were no further recurrences. Depression scores improved more gradually to remission at session 10. Full remission from depression and binge-eating/purging episodes was sustained more than 2 months after treatment completion. In neuroimaging studies, the DMPFC is important in impulse control, and is underactive in BN. DMPFC–rTMS may have enhanced the patient’s ability to deploy previously acquired strategies to avoid binge-eating and purging via a reduction in her impulsivity. A larger sham-controlled trial of DMPFC–rTMS for binge-eating and purging behavior may be warranted.

The Canadian Biomarker Integration Network in Depression (CAN-BIND): Advances in Response Prediction

Identifying biological and clinical markers of treatment response in depression is an area of intense research that holds promise for increasing the efficiency and efficacy of resolving a major depressive episode and preventing future episodes. Collateral benefits include decreased healthcare costs and increased workplace productivity. Despite research advances in many areas, efforts to identify biomarkers have not revealed any consistently validated candidates. Studies of clinical characteristics, genetic, neuroimaging, and various biochemical markers have all shown promise in discrete studies, but these findings have not translated into a personalized medicine approach to treating individual patients in the clinic. We propose that an integrated study of a range of biomarker candidates from across different modalities is required. Furthermore, advanced mathematical modeling and pattern recognition methods are required to detect important biological signatures associated with treatment outcome. Through an informatics-based integration of the various clinical, molecular and imaging parameters that are known to be important in the pathophysiology of depression, it becomes possible to encompass the complexity of contributing factors and phenotypic presentations of depression, and identify the key signatures of treatment response.

Reductions in Cortico-Striatal Hyperconnectivity Accompany Successful Treatment of Obsessive-Compulsive Disorder with Dorsomedial Prefrontal rTMS

Obsessive-compulsive disorder (OCD) is a disabling illness with high rates of nonresponse to conventional treatments. OCD pathophysiology is believed to involve abnormalities in cortico-striatal-thalamic-cortical circuits through regions such as dorsomedial prefrontal cortex (dmPFC) and ventral striatum. These regions may constitute therapeutic targets for neuromodulation treatments, such as repetitive transcranial magnetic stimulation (rTMS). However, the neurobiological predictors and correlates of successful rTMS treatment for OCD are unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) to identify neural predictors and correlates of response to 20–30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls as baseline comparators. A region of interest in the dmPFC was used to generate whole-brain functional connectivity maps pre-treatment and post treatment. Ten of 20 patients met the response criteria (⩾50% improvement on Yale-Brown Obsessive-Compulsive Scale, YBOCS); response to dmPFC-rTMS was sharply bimodal. dmPFC-rTMS responders had higher dmPFC-ventral striatal connectivity at baseline. The degree of reduction in this connectivity, from pre- to post-treatment, correlated to the degree of YBOCS symptomatic improvement. Baseline clinical and psychometric data did not predict treatment response. In summary, reductions in fronto-striatal hyperconnectivity were associated with treatment response to dmPFC-rTMS in OCD. This finding is consistent with previous fMRI studies of deep brain stimulation in OCD, but opposite to previous reports on mechanisms of dmPFC-rTMS in major depression. fMRI could prove useful in predicting the response to dmPFC-rTMS in OCD.