Personalized prediction of transcranial magnetic stimulation clinical response in patients with treatment-refractory depression using neuroimaging biomarkers and machine learning.

BACKGROUND: Functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and subgenual cingulate (sgACC) may serve as a biomarker for transcranial magnetic stimulation (rTMS) treatment response. The first aim was to establish whether this finding is veridical or artifactually induced by the pre-processing method. Furthermore, alternative biomarkers were identified and the clinical utility for personalized medicine was examined. METHODS: Resting-state fMRI data were collected in medication-refractory depressed patients (n = 70, 16 males) before undergoing neuronavigated left DLPFC rTMS. Seed-based analyses were performed with and without global signal regression pre-processing to identify biomarkers of short-term and long-term treatment response. Receiver Operating Characteristic curve and supervised machine learning analyses were applied to assess the clinical utility of these biomarkers for the classification of categorical rTMS response. RESULTS: Regardless of the pre-processing method, DLPFC-sgACC connectivity was not associated with treatment outcome. Instead, poorer connectivity between the sgACC and three clusters (peak locations: frontal pole, superior parietal lobule, occipital cortex) and DLPFC-central opercular cortex were observed in long-term nonresponders. The identified connections could serve as acceptable to excellent markers. Combining the features using supervised machine learning reached accuracy rates of 95.35% (CI=82.94-100.00) and 88.89% (CI=63.96-100.00) in the cross-validation and test dataset, respectively. LIMITATIONS: The sample size was moderate, and features for machine learning were based on group differences. CONCLUSIONS: Long-term nonresponders showed greater disrupted connectivity in regions involving the central executive network. Our findings may aid the development of personalized medicine for medication-refractory depression.

[Non-invasive brain stimulation in schizophrenia: hallucinations and negative symptoms]. / Non-invasieve hersenstimulatie bij schizofrenie, gericht op hallucinaties en negatieve symptomen.

BACKGROUND: New approaches are needed in the treatment of characteristic symptoms of schizophrenia such as hallucinations and negative symptoms. Non-invasive brain stimulation can make a useful contribution.
AIM: To discuss the published evidence regarding efficacy and safety of repetitive transcranial magnetic stimulation (rtms) and transcranial direct current stimulation (tdcs) when used in the treatment of auditory verbal hallucinations and negative symptoms.
METHOD: We review and discuss recent meta-analyses and we analyse relevant factors.
RESULTS: On average, when compared to sham-stimulation, rtms was found to have a significant effect on hallucinations and negative symptoms. Nevertheless, the results of some studies were variable and some studies did not report any improvement. There are indications that some factors such as age and distance between scalp and cortex may influence efficiency. There were only a few studies relating to the use of tdcs and none of these reported a clear effect.
CONCLUSION: There is reasonable evidence that rtms is an efficient treatment for hallucinations and negative symptoms, although some variable results have been reported. There is insufficient evidence for conclusions to be drawn about the efficacy of tdcs for the treatment of hallucinations and negative symptoms. However, both simulation methods are safe and largely without side-effects.

Detection of lactate in the striatum without contamination of macromolecules by J-difference editing MRS at 7T.

Lactate levels are measurable by MRS and are related to neural activity. Therefore, it is of interest to accurately measure lactate levels in the basal ganglia networks. If sufficiently stable, lactate measurements may be used to investigate alterations in dopaminergic signalling in the striatum, facilitating the detection and diagnosis of metabolic deficits. The aim of this study is to provide a J-difference editing MRS technique for the selective editing of lactate only, thus allowing the detection of lactate without contamination of overlapping macromolecules. As a validation procedure, macromolecule nulling was combined with J-difference editing, and this was compared with J-difference editing with a new highly selective editing pulse. The use of a high-field (7T) MR scanner enables the application of editing pulses with very narrow bandwidth, which are selective for lactate. We show that, despite the sensitivity to B0 offsets, the use of a highly selective editing pulse is more efficient for the detection of lactate than the combination of a broad-band editing pulse with macromolecule nulling. Although the signal-to-noise ratio of uncontaminated lactate detection in healthy subjects is relatively low, this article describes the test-retest performance of lactate detection in the striatum when using highly selective J-difference editing MRS at 7 T. The coefficient of variation, σw and intraclass correlation coefficients for within- and between-subject differences of lactate were determined. Lactate levels in the left and right striatum were determined twice in 10 healthy volunteers. Despite the fact that the test-retest performance of lactate detection is moderate with a coefficient of variation of about 20% for lactate, these values can be used for the design of new studies comparing, for example, patient populations with healthy controls.

Comparative diffusion tractography of corticostriatal motor pathways reveals differences between humans and macaques.

The primate corticobasal ganglia circuits are understood to be segregated into parallel anatomically and functionally distinct loops. Anatomical and physiological studies in macaque monkeys are summarized as showing that an oculomotor loop begins with projections from the frontal eye fields (FEF) to the caudate nucleus, and a motor loop begins with projections from the primary motor cortex (M1) to the putamen. However, recent functional and structural neuroimaging studies of the human corticostriatal system report evidence inconsistent with this organization. To obtain conclusive evidence, we directly compared the pattern of connectivity between cortical motor areas and the striatum in humans and macaques in vivo using probabilistic diffusion tractography. In macaques we found that FEF is connected with the head of the caudate and anterior putamen, and M1 is connected with more posterior sections of the caudate and putamen, corroborating neuroanatomical tract tracing findings. However, in humans FEF and M1 are connected to largely overlapping portions of posterior putamen and only a small portion of the caudate. These results demonstrate that the corticobasal connectivity for the oculomotor and primary motor loop is not entirely segregated for primates at a macroscopic level and that the description of the anatomical connectivity of corticostriatal motor systems in humans does not parallel that of macaques, perhaps because of an expansion of prefrontal projections to striatum in humans.

TMS of the anterior intraparietal area selectively modulates orientation change detection during action preparation.

Perception of relevant visual object features can be modulated by the preparation of an action toward it ("action-modulated perception"). For instance, the perception of the orientation of a book can be enhanced when preparing to grasp it (but not when pointing to it). However, the underlying neuronal mechanisms are poorly understood. We argue that brain areas controlling arm movements are involved in establishing this effect through top-down feedback to early visual areas, similar to the neuronal mechanisms linking visual attention and eye movements. To investigate this involvement, we applied transcranial magnetic stimulation to a grasping motor area, the left anterior intraparietal sulcus (aIPS), during grasping or pointing preparation. Concurrently, an orientation change detection task was performed. As a control area, the vertex was stimulated. We found that stimulation of aIPS selectively modulates orientation sensitivity during action preparation compared with control stimulation (vertex), negating the increased orientation sensitivity with grasping preparation over pointing preparation. We argue that aIPS is a critical part of the mechanism underlying perceptual modulations during action preparation. The present results and recent literature suggest that this action-modulated perception for hand movements is implemented through a cortical feedback connection between aIPS and early visual areas.

Reproducibility of brain activation during auditory verbal hallucinations.

Previous studies investigated fMRI-guided repetitive Transcranial Magnetic Stimulation (rTMS) as an alternative treatment for auditory verbal hallucinations (AVH). This tailor-made treatment focuses at directing the rTMS coil to the location where hallucinatory activation is maximal, as identified with fMRI scans of individual patients. For the effective use of such treatment it is important to determine whether brain activation during AVH can be reliably detected using fMRI. Thirty-three psychotic patients indicated the presence of AVH during two subsequent scans. Reproducibility was measured by calculating 1) the distance between local maxima of significantly activated clusters and 2) percentage overlap of activation patterns over the two scans. These measurements were obtained both in single subjects and on group-level in five regions of interest (ROIs). ROIs consisted of the areas that were most frequently activated during AVH. Scans were considered reproducible if the distance between local maxima was smaller than 2 cm, as rTMS-treatment may target an area of approximately 2-4 cm. The median distance between local maxima was smaller than 2 cm for all ROIs on single-subject level, as well as on group-level. In addition, on single-subject level median percentage overlap varied between 14 and 38% for the different ROIs. On group-level, this was substantially higher with percentages overlap varying between 34 and 98%. Based on these results, AVH-scans may be considered sufficiently reproducible to be suitable for fMRI-guided rTMS treatment.

The role of the frontal eye fields in oculomotor competition: image-guided TMS enhances contralateral target selection.

In order to execute a correct eye movement to a target in a search display, a saccade program toward the target element must be activated, while saccade programs toward distracting elements must be inhibited. The aim of the present study was to elucidate the role of the frontal eye fields (FEFs) in oculomotor competition. Functional magnetic resonance imaging-guided single-pulse transcranial magnetic stimulation (TMS) was administered over either the left FEF, the right FEF, or the vertex (control site) at 3 time intervals after target presentation, while subjects performed an oculomotor capture task. When TMS was applied over the FEF contralateral to the visual field where a target was presented, there was less interference of an ipsilateral distractor compared with FEF stimulation ipsilateral to the target's visual field or TMS over vertex. Furthermore, TMS over the FEFs decreased latencies of saccades to the contralateral visual field, irrespective of whether the saccade was directed to the target or to the distractor. These findings show that single-pulse TMS over the FEFs enhances the selection of a target in the contralateral visual field and decreases saccade latencies to the contralateral visual field.

Aberrant resting-state connectivity in non-psychotic individuals with auditory hallucinations.

BACKGROUND: Although auditory verbal hallucinations (AVH) are a core symptom of schizophrenia, they also occur in non-psychotic individuals, in the absence of other psychotic, affective, cognitive and negative symptoms. AVH have been hypothesized to result from deviant integration of inferior frontal, parahippocampal and superior temporal brain areas. However, a direct link between dysfunctional connectivity and AVH has not yet been established. To determine whether hallucinations are indeed related to aberrant connectivity, AVH should be studied in isolation, for example in non-psychotic individuals with AVH. METHOD: Resting-state connectivity was investigated in 25 non-psychotic subjects with AVH and 25 matched control subjects using seed regression analysis with the (1) left and (2) right inferior frontal, (3) left and (4) right superior temporal and (5) left parahippocampal areas as the seed regions. To correct for cardiorespiratory (CR) pulsatility rhythms in the functional magnetic resonance imaging (fMRI) data, heartbeat and respiration were monitored during scanning and the fMRI data were corrected for these rhythms using the image-based method for retrospective correction of physiological motion effects RETROICOR. RESULTS: In comparison with the control group, non-psychotic individuals with AVH showed increased connectivity between the left and the right superior temporal regions and also between the left parahippocampal region and the left inferior frontal gyrus. Moreover, this group did not show a negative correlation between the left superior temporal region and the right inferior frontal region, as was observed in the healthy control group. CONCLUSIONS: Aberrant connectivity of frontal, parahippocampal and superior temporal brain areas can be specifically related to the predisposition to hallucinate in the auditory domain.

Microstructural alterations of the arcuate fasciculus in schizophrenia patients with frequent auditory verbal hallucinations.

Auditory verbal hallucinations (AVH) is a common and stressful symptom of schizophrenia. Disrupted connectivity between frontal and temporo-parietal language areas, giving rise to the misattribution of inner speech, is speculated to underlie this phenomenon. Disrupted connectivity should be reflected in the microstructure of the arcuate fasciculi (AF); the main connection between frontal and temporo-parietal language areas. In this study we compared microstructural properties of the AF and three other fiber tracts (cortical spinal tract, cingulum and uncinate fasciculus), between 44 schizophrenia patients with chronic severe hallucinations and 42 control subjects using diffusion tensor imaging (DTI) and magnetic transfer imaging (MTI). The DTI scans were used to compute fractional anisotropy (FA) and to reconstruct the fiber bundles of interest, while the MTI scans were used to compute magnetic transfer ratio (MTR) values. The patient group showed a general decrease in FA for all bundles. In the arcuate fasciculus this decreased FA was coupled to a significant increase in MTR values. A correlation was found between mean MTR values in both arcuate fasciculi and the severity of positive symptoms. The combination of decreased FA and increased MTR values observed in the arcuate fasciculi in patients suggests increased free water concentrations, probably caused by degraded integrity of the axons or the supportive glia cells. This suggests that disintegrated fiber integrity in the connection between frontal and temporo-parietal language areas in the schizophrenia patients is associated with their liability for auditory verbal hallucinations.

Neural and temporal dynamics underlying visual selection for action.

The present study investigated the selection for action hypothesis, according to which a subject's action intention to perform a movement influences the way in which visual information is being processed. Subjects were instructed in separate blocks either to grasp or to point to a three-dimensional target-object and event-related potentials were recorded relative to stimulus onset. It was found that grasping compared with pointing resulted in a stronger N1 component and a subsequent selection negativity, which were localized to the lateral occipital complex. These effects suggest that the intention to grasp influences the processing of action-relevant features in ventral stream areas already at an early stage (e.g., enhanced processing of object orientation for grasping). These findings provide new insight in the neural and temporal dynamics underlying perception-action coupling and provide neural evidence for a selection for action principle in early human visual processing.

fMRI-guided TMS on cortical eye fields: the frontal but not intraparietal eye fields regulate the coupling between visuospatial attention and eye movements.

It is well known that parts of a visual scene are prioritized for visual processing, depending on the current situation. How the CNS moves this focus of attention across the visual image is largely unknown, although there is substantial evidence that preparation of an action is a key factor. Our results support the view that direct corticocortical feedback connections from frontal oculomotor areas to the visual cortex are responsible for the coupling between eye movements and shifts of visuospatial attention. Functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) was applied to the frontal eye fields (FEFs) and intraparietal sulcus (IPS). A single pulse was delivered 60, 30, or 0 ms before a discrimination target was presented at, or next to, the target of a saccade in preparation. Results showed that the known enhancement of discrimination performance specific to locations to which eye movements are being prepared was enhanced by early TMS on the FEF contralateral to eye movement direction, whereas TMS on the IPS resulted in a general performance increase. The current findings indicate that the FEF affects selective visual processing within the visual cortex itself through direct feedback projections.

TMS pulses on the frontal eye fields break coupling between visuospatial attention and eye movements.

While preparing a saccadic eye movement, visual processing of the saccade goal is prioritized. Here, we provide evidence that the frontal eye fields (FEFs) are responsible for this coupling between eye movements and shifts of visuospatial attention. Functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) was applied to the FEFs 30 ms before a discrimination target was presented at or next to the target of a saccade in preparation. Results showed that the well-known enhancement of discrimination performance on locations to which eye movements are being prepared was diminished by TMS contralateral to eye movement direction. Based on the present and other reports, we propose that saccade preparatory processes in the FEF affect selective visual processing within the visual cortex through feedback projections, in that way coupling saccade preparation and visuospatial attention.

Interactions between ego- and allocentric neuronal representations of space.

In the primate brain, visual spatial representations express distances of objects with regard to different references. In the parietal cortex, distances are thought to be represented with respect to the body (egocentric representation) and in superior temporal cortices with respect to other objects, independent of the observer (allocentric representation). However, these representations of space are interdependent, complicating such distinctions. Specifically, an object's position within a background frame strongly biases egocentric position location judgments. This bias, however, is absent for pointing movements towards that same object. More recent theories state that dorsal parietal spatial representations subserve visuomotor processing, whereas temporal lobe representations subserve memory and cognition. Therefore, it may be hypothesized that parietal egocentric representations, responsible for movement control, are not influenced by irrelevant allocentric cues, whereas ventral representations are. In an event-related functional magnetic resonance imaging study, subjects judged target bar locations relative to their body (egocentric task) or a background bar (allocentric task). Activity in the superior parietal lobule (SPL) was shown to increase during egocentric judgments, but not during allocentric judgments. The superior temporal gyrus (STG) shows a negative BOLD response during allocentric judgments and no activation during egocentric judgments. During egocentric judgments, the irrelevant background influenced activity in the posterior commissure and the medial temporal gyrus. SPL activity was unaffected by the irrelevant background during egocentric judgments. Sensitivity to spatial perceptual biases is apparently limited to occipito-temporal areas, subserving the observed biased cognitive reports of location, and is not found in parietal areas, subserving unbiased goal-directed actions.

Cortical and subcortical contributions to saccade latency in the human brain.

An important property of our motor system is the ability to either perform or inhibit an automatic goal-directed reaction. Imagine, for example, how easily we can catch a ball, while at the same time we would never grasp a stinging insect approaching us. The oculomotor system provides a good model to study this ability. Monkey midbrain superior colliculus neurons are responsible for automatic visually evoked saccades, whereas the frontal eye fields can prevent reflexive glances. Little is known about human superior colliculus or the competition between the midbrain and frontal areas controlling saccades. In the present functional magnetic resonance study we used the gap paradigm, where a stimulus fixated with the eyes is removed 200 ms prior to saccade target onset. Subjects were required to either look at the target or prevent an eye movement. From what is known from non-human primate neurophysiology, it is expected that the gap will result in enlarged neuronal activity in the human superior colliculus, disinhibiting the oculomotor system and enhancing automatic reactions. Importantly, we demonstrate that the human superior colliculus homologue is indeed activated by the removal of a fixation target, in either task. The frontal eye fields show a reverse pattern when saccades were suppressed. Furthermore, magnitude of responses in the superior colliculus correlated negatively with saccade latency, and in the frontal eye fields positively. These findings confirm for the first time that the human superior colliculus generates automatic goal-directed saccades, whereas the frontal eye fields can exert volitional control over automatic orienting.

A stereotactic method for image-guided transcranial magnetic stimulation validated with fMRI and motor-evoked potentials.

Transcranial Magnetic Stimulation (TMS) delivers short magnetic pulses that penetrate the skull unattenuated, disrupting neural processing in a noninvasive, reversible way. To disrupt specific neural processes, coil placement over the proper site is critical. Therefore, a neural navigator (NeNa) was developed. NeNa is a frameless stereotactic device using structural and functional magnetic resonance imaging (fMRI) data to guide TMS coil placement. To coregister the participant's head to his MRI, 3D cursors are moved to anatomical landmarks on a skin rendering of the participants MRI on a screen, and measured at the head with a position measurement device. A method is proposed to calculate a rigid body transformation that can coregister both sets of coordinates under realistic noise conditions. After coregistration, NeNa visualizes in real time where the device is located with respect to the head, brain structures, and activated areas, enabling precise placement of the TMS coil over a predefined target region. NeNa was validated by stimulating 5 x 5 positions around the 'motor hotspot' (thumb movement area), which was marked on the scalp guided by individual fMRI data, while recording motor-evoked potentials (MEPs) from the abductor pollicis brevis (APB). The distance between the center of gravity (CoG) of MEP responses and the location marked on the scalp overlying maximum fMRI activation was on average less then 5 mm. The present results demonstrate that NeNa is a reliable method for image-guided TMS coil placement.

Coordinated control of eye and hand movements in dynamic reaching.

In the present study, we integrated two recent, at first sight contradictory findings regarding the question whether saccadic eye movements can be generated to a newly presented target during an ongoing hand movement. Saccades were measured during so-called adaptive and sustained pointing conditions. In the adapted pointing condition, subjects had to direct both their gaze and arm movements to a displaced target location. The results showed that the eyes could fixate the new target during pointing. In addition, a temporal coupling of these corrective saccades was found with changes in arm movement trajectories when reaching to the new target. In the sustained pointing condition, however, the same subjects had to point to the initial target, while trying to deviate their gaze to a new target that appeared during pointing. It was found that the eyes could not fixate the new target before the hand reached the initial target location. Together, the results indicate that ocular gaze is always forced to follow the target intended by a manual arm movement. A neural mechanism is proposed that couples ocular gaze to the target of an arm movement. Specifically, the mechanism includes a reach neuron layer besides the well-known saccadic layer in the primate superior colliculus. Such a tight, sub-cortical coupling of ocular gaze to the target of a reaching movement can explain the contrasting behavior of the eyes in dependency of whether the eye and hand share the same target position or attempt to move to different locations.