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The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5–8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level‐dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre‐treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85–95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p

Pain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure—the insertion of an elastomeric separator between teeth—which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity (rsFC) of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional (rs-fMRI) scanning prior to the placement of a separator between the first and second molars, which was kept in place for five days. Participants recorded pain ratings three times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve, or grey matter volume of any brain region. Peak pain did, however, positively correlate with baseline rsFC between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, pre-interventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48-1.90; p.0001-0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed.

We discuss the value of resting-state functional MR imaging (rsfMR imaging) as an emerging technique to address questions about memory and language that are central in surgery for temporal-lobe epilepsy, namely the identification and characterization of eloquent cortex to avoid surgical morbidity. The emergence of a robust set of data using rsfMR imaging has opened new avenues for exploring more direct relationships between neural networks and current cognitive function and prediction of postoperative change. These techniques are also being explored for their potential to characterize epilepsy subtypes, identify epileptic foci, and monitor treatment effects.

We have previously shown that the connectivity of the hippocampus to other regions of the default mode network (DMN) is a strong indicator of memory ability in people with temporal lobe epilepsy (TLE). Recent work in the cognitive neuroscience literature has suggested that the anterior and posterior aspects of the hippocampus have distinct connections to the rest of the DMN and may support different memory operations. Further, structural analysis of epileptogenic hippocampi has found greater atrophy, characterized by mesial temporal sclerosis, in the anterior region of the hippocampus. Here, we used resting state FMRI data to parcellate the hippocampus according to its functional connectivity to the rest of the brain in people with left lateralized TLE (LTLE) and right lateralized TLE (RTLE), and in a group of neurologically healthy controls. We found similar anterior and posterior compartments in all groups. However, there was weaker connectivity of the epileptogenic hippocampus to multiple regions of the DMN. Both TLE groups showed reduced connectivity of the posterior hippocampus to key hubs of the DMN, the posterior cingulate cortex (PCC) and the medial pre-frontal cortex (mPFC). In the LTLE group, the anterior hippocampus also showed reduced connectivity to the DMN, and this effect was influenced by the presence of mesial temporal sclerosis. When we explored brain-behavior relationships, we found that reduced connectivity of the left anterior hippocampus to the DMN hubs related to poorer verbal memory ability in people with LTLE, and reduced connectivity of the right posterior hippocampus to the PCC related to poorer visual memory ability in those with RTLE. These findings may inform models regarding functional distinctions of the hippocampal anteroposterior axis.

Recent neuroimaging studies implicate the medial temporal lobe (MTL) in nociception and pain modulation. Here, we aim to identify which subregions of the MTL are involved in human pain and to test its connectivity in a cohort of chronic low-back pain patients (CBP). We conducted 2 coordinate-based meta-analyses to determine which regions within the MTL showed consistent spatial patterns of functional activation (1) in response to experimental pain in healthy participants and (2) in chronic pain compared with healthy participants. We followed PRISMA guidelines and performed activation likelihood estimate (ALE) meta-analyses. The first meta-analysis revealed consistent activation in the right anterior hippocampus (right antHC), parahippocampal gyrus, and amygdala. The second meta-analysis revealed consistently less activation in patients' right antHC, compared with healthy participants. We then conducted a seed-to-voxel resting state functional connectivity of the right antHC seed with the rest of the brain in 77 CBP and 79 age-matched healthy participants. We found that CBP had significantly weaker antHC functional connectivity to the medial prefrontal cortex compared with healthy participants. Taken together, these data indicate that the antHC has abnormally lower activity in chronic pain and reduced connectivity to the medial prefrontal cortex in CBP. Future studies should investigate the specific role of the antHC in the development and management of chronic pain.

Hallucinations are common in Parkinson’s disease (PD). Based on functional brain MRI data, hallucinations are proposed to result from alterations in the dorsal attention network (DAN), ventral attention network (VAN), and default mode network. Using structural MRI data from Parkinson’s Progression Markers Initiative (PPMI), we examined cortical thickness in these networks in PD patients with (n=30) and without (n=30) minor hallucinations who were matched on multiple clinical characteristics (e.g., age, sex, education, cognitive diagnosis, MoCA score, medication, disease duration, and severity) as well as healthy controls (n=30) matched on demographic variables. Multivariate analyses revealed mild hallucinations to be associated with thicker cortex in the DAN and VAN, and these effects were driven by the left superior precentral sulcus and postcentral sulcus for the DAN and by the right insular gyrus for the VAN. While these findings may seem at odds with prior work showing grey matter reductions, our patients are in earlier stages of the disease than those in other studies. This is consistent with an inverted U-shape pattern of cortical thickness alterations in other neurodegenerative diseases and warrants further investigations in longitudinal studies tracking brain correlates of PD psychosis progression.

While anterior temporal lobe (ATL) resection is an effective treatment for temporal lobe epilepsy, surgery on the dominant hemisphere is associated with variable decline in confrontation naming. Accurate prediction of naming impairment is critical to inform clinical decision making, and while there has been some degree of success using task-based functional MRI (fMRI) paradigms, there remains a growing interest in the predictive utility of resting-state connectivity as it allows for relatively shorter scans with low task demands. Our objective was to assess the relationship between measures of preoperative resting-state connectivity and postoperative naming change in patients following left ATL resection. We compared the resting language network connectivity of each patient to a normative healthy control template using a novel measure called "matrix similarity," and found that patients with more abnormal global language-network connectivity-particularly of regions spared from surgery-showed greater postoperative naming decline than those with normative patterns of connectivity. When we interrogated the degree centrality of to-be-resected regions in a more targeted approach of the pathological temporal lobe, we found that greater functional integration of those regions with the rest of the language network at rest was related to greater decline in naming following surgery. Finally, we found that matrix similarity was a better predictor of postoperative outcome than degree within to-be-resected regions, network clustering, modularity, and language task fMRI laterality. We provide some of the first evidence that using this novel measure, a relatively short preoperative resting scan can be exploited to inform naming ability following ATL resection.

Individuals with medial temporal lobe epilepsy (mTLE) often show material-specific memory impairment (verbal for left, visuospatial for right hemisphere) which can be exacerbated following surgery aimed at the epileptogenic regions of medial and anterolateral temporal cortex. There is a growing body of evidence suggesting that characterization of structural and functional integrity of these regions using MRI can aid in prediction of post-surgical risk of further memory decline. We investigated the nature of the relationship between structural and functional indices of hippocampal integrity with preoperative memory performance in a group of 26 patients with unilateral mTLE. Structural integrity was assessed using hippocampal volumes, while functional integrity was assessed using hippocampal activation during the encoding of novel scenes. We quantified structural and functional integrity in terms of asymmetry, calculated as (L - R) / (L + R). Factor scores for verbal and visual memory were calculated from a clinical database and an asymmetry score (verbal – visual) was used to characterize memory performance. We found, as expected, a significant difference between left and right mTLE groups for hippocampal volume asymmetry, with each group showing an asymmetry favoring the unaffected temporal lobe. Encoding activation asymmetry showed a similar pattern, with left mTLE patients showing activation preferential to the right hemisphere and right mTLE patients showing the reverse. Finally, we demonstrated that functional integrity mediated the relationship between structural integrity and memory performance for memory asymmetry, suggesting that even if structural changes are evident, ultimately it is the functional integrity of the tissue that most closely explains behavioral performance. Our findings argue for the incorporation of functional imaging data in clinical protocols aimed at determining the functional integrity of the MTL in surgical planning.

Computational models predict that focal damage to the Default Mode Network (DMN) causes widespread decreases and increases of functional DMN connectivity. How such alterations impact functioning in a specific cognitive domain such as episodic memory remains relatively unexplored. Here, we show in patients with unilateral medial temporal lobe epilepsy (mTLE) that focal structural damage leads indeed to specific patterns of DMN functional connectivity alterations, specifically decreased connectivity between both medial temporal lobes (MTLs) and the posterior part of the DMN and increased intrahemispheric anterior–posterior connectivity. Importantly, these patterns were associated with better and worse episodic memory capacity, respectively. These distinct patterns, shown here for the first time, suggest that a close dialogue between both MTLs and the posterior components of the DMN is required to fully express the extensive repertoire of episodic memory abilities., Highlights • Focal structural damage correlates with widespread functional change in DMN in mTLE. • Greater DMN connectivity alterations reflect worse clinical memory measures. • Structural integrity moderates influence of functional connectivity on memory. • Interhemispheric integration of MTL into posterior DMN may be key to better memory.

fMRI language mapping has become increasingly utilized for determining language dominance before surgical intervention for temporal lobe epilepsy (TLE). This study aimed to examine the differences between two classes of fMRI word generation tasks used in our clinic: tasks using a single word cue, referred to as simple generative tasks (SGTs), and tasks also involving sentence-level processing, referred to as sentence-level language tasks (SLTs). Specifically, we aimed to investigate the extent and laterality of activation and frontal-temporal connectivity during these language tasks and their relationship to clinical language measures. Thirty-one patients with TLE (18 patients with left TLE and 13 patients with right TLE) performed four language tasks during an fMRI scan, two SGTs and two SLTs. We found significantly greater activity for SLTs over SGTs in bilateral inferior frontal and middle temporal gyri and the left temporal pole. Sentence-level language tasks also showed greater lateralization compared with SGTs. Finally, we found that while activation extent did not correlate with clinical language tests, the degree of left frontal-temporal connectivity was significantly correlated with naming and semantic fluency performance. These correlations also were more robust for SLTs than for SGTs. Taken together, these results provide a compelling argument for including some form of SLTs in fMRI language lateralization protocols for TLE as they allow for better characterization of language networks, particularly in the temporal lobes which are at risk in surgery.