mri-guided-dmpfc-rtms-as-treatment-for-treatment-resistant-major

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

University of Toronto

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.

Resting-state cortico-thalamic-striatal connectivity predicts response to dorsomedial prefrontal rTMS in major depressive disorder.

Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes.

Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.

The frontal pole corresponds to Brodmann area (BA) 10, the largest single architectonic area in the human frontal lobe. Generally, BA10 is thought to contain two or three subregions that subserve broad functions such as multitasking, social cognition, attention, and episodic memory. However, there is a substantial debate about the functional and structural heterogeneity of this large frontal region. Previous connectivity-based parcellation studies have identified two or three subregions in the human frontal pole. Here, we used diffusion tensor imaging to assess structural connectivity of BA10 in 35 healthy subjects and delineated subregions based on this connectivity. This allowed us to determine the correspondence of structurally based subregions with the scheme previously defined functionally. Three subregions could be defined in each subject. However, these three subregions were not spatially consistent between subjects. Therefore, we accepted a solution with two subregions that encompassed the lateral and medial frontal pole. We then examined resting-state functional connectivity of the two subregions and found significant differences between their connectivities. The medial cluster was connected to nodes of the default-mode network, which is implicated in internally focused, self-related thought, and social cognition. The lateral cluster was connected to nodes of the executive control network, associated with directed attention and working memory. These findings support the concept that there are two major anatomical subregions of the frontal pole related to differences in functional connectivity.

Connectivity-based parcellation of the human frontal polar cortex.

The default mode network (DMN) describes a distributed network of brain regions that are predominantly activated and engaged during periods of spontaneous, stimulus independent thought (i.e., at rest) and remain quiescent during attention-demanding, goal-directed tasks. Replicated evidence in functional neuroimaging studies suggests that midline cortical and subcortical brain regions responsible for memory, self-relevant emotional and mental processes, as well as information integration comprise the DMN. The DMN is posited to represent self-referential mental activity via a dynamic interplay of cognitive and emotional processes by integrating information from the external environment with introspective thoughts to generate an autobiographical concept of the self. It has been amply documented that irregularities in the DMN and its functional connectivity are associated with various neuropsychiatric disorders. Moreover, accumulating evidence also suggests that individuals with select medical disorders (i.e., metabolic disorders) demonstrate alterations in DMN activity and functional connectivity. However, there is a paucity of data evaluating whether individuals with metabolically-based medical conditions, exhibiting altered DMN activity and functional connectivity, are at increased risk for developing neuropsychiatric disorders. Likewise, potential mechanisms (e.g., altered brain metabolism, insulin resistance) mediating these changes and their implications for novel treatment approaches have yet to be elucidated. Taken together, the overarching aim of this review is to provide a synthetic overview that suggests that this neural circuit may represent a common (or convergent) substrate affected in individuals with select neuropsychiatric and metabolic disorders.

The putative impact of metabolic health on default mode network activity and functional connectivity in neuropsychiatric disorders.

Conventional treatments for eating disorders are associated with poor response rates and frequent relapse. Novel treatments are needed, in combination with markers to characterize and predict treatment response. Here, resting-state functional magnetic resonance imaging (rs-fMRI) was used to identify predictors and correlates of response to repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (dmPFC) at 10 Hz for eating disorders with refractory binge/purge symptomatology.

Increases in frontostriatal connectivity are associated with response to dorsomedial repetitive transcranial magnetic stimulation in refractory binge/purge behaviors.

Article	Year
Resting-state cortico-thalamic-striatal connectivity predicts response to dorsomedial prefrontal rTMS in major depressive disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 24150516	2014
Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biological psychiatry\| PubMed ID: 24388670	2014
Connectivity-based parcellation of the human frontal polar cortex. Brain structure & function\| PubMed ID: 24927720	2014
The putative impact of metabolic health on default mode network activity and functional connectivity in neuropsychiatric disorders. CNS & neurological disorders drug targets\| PubMed ID: 25470392	2014
Increases in frontostriatal connectivity are associated with response to dorsomedial repetitive transcranial magnetic stimulation in refractory binge/purge behaviors. NeuroImage. Clinical\| PubMed ID: 26199873	2015

Katharine Dunlop

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