Effects of transcranial magnetic stimulation on the human brain recorded with intracranial electrocorticography.

Transcranial magnetic stimulation (TMS) is increasingly used as a noninvasive technique for neuromodulation in research and clinical applications, yet its mechanisms are not well understood. Here, we present the neurophysiological effects of TMS using intracranial electrocorticography (iEEG) in neurosurgical patients. We first evaluated safety in a gel-based phantom. We then performed TMS-iEEG in 22 neurosurgical participants with no adverse events. We next evaluated intracranial responses to single pulses of TMS to the dorsolateral prefrontal cortex (dlPFC) (N = 10, 1414 electrodes). We demonstrate that TMS is capable of inducing evoked potentials both locally within the dlPFC and in downstream regions functionally connected to the dlPFC, including the anterior cingulate and insular cortex. These downstream effects were not observed when stimulating other distant brain regions. Intracranial dlPFC electrical stimulation had similar timing and downstream effects as TMS. These findings support the safety and promise of TMS-iEEG in humans to examine local and network-level effects of TMS with higher spatiotemporal resolution than currently available methods.

TMS provokes target-dependent intracranial rhythms across human cortical and subcortical sites.

Transcranial magnetic stimulation (TMS) is increasingly deployed in the treatment of neuropsychiatric illness, under the presumption that stimulation of specific cortical targets can alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach is most useful for evaluating low-frequency neural activity at the cortical surface. As such, little is known about how TMS perturbs rhythmic activity among deeper structures - such as the hippocampus and amygdala - and whether stimulation can alter higher-frequency oscillations. Recent work has established that TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct neural recordings at sufficient spatiotemporal resolution to examine localized oscillatory responses across the frequency spectrum. To that end, we recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at several cortical sites. Stimulation to the dorsolateral prefrontal cortex (DLPFC) drove widespread low-frequency increases (3-8Hz) in frontolimbic cortices, as well as high-frequency decreases (30-110Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with brief evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. Taken together, we established that non-invasive stimulation can (1) provoke a mixture of low-frequency evoked power and induced theta oscillations and (2) suppress high-frequency activity in deeper brain structures not directly accessed by stimulation itself.

Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies.

Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer's disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.

Rapid eye movement sleep patterns of brain activation and deactivation occur within unique functional networks.

Rapid eye movement (REM) sleep is a paradoxical state where the individual appears asleep while the electroencephalogram pattern resembles that of wakefulness. Regional differences in brain metabolism have been observed during REM sleep compared to wakefulness, but it is not known whether the spatial distribution of metabolic differences corresponds to known functional networks in the brain. Here, we use a combination of techniques to evaluate the networks associated with sites of REM sleep activation and deactivation from previously published positron emission tomography studies. We use seed-based functional connectivity from healthy adults acquired during quiet rest to show that REM-activation regions are functionally connected in a network that includes retrosplenial cingulate cortex, parahippocampal gyrus, and extrastriate visual cortices, corresponding to components of the default mode network and visual networks. Regions deactivated during REM sleep localize to right-lateralized fronto-parietal and salience networks. A negatively correlated relationship was observed between REM-activation and deactivation networks. Together, these findings show that regional activation and deactivation patterns of REM sleep tend to occur in distinct functional connectivity networks that are present during wakefulness, providing insights regarding the differential contributions of brain regions to the distinct subjective experiences that occur during REM sleep (dreaming) relative to wakefulness.

Reliability of targeting methods in TMS for depression: Beam F3 vs. 5.5 cm.

BACKGROUND: No consensus exists in the clinical transcranial magnetic stimulation (TMS) field as to the best method for targeting the left dorsolateral prefrontal cortex (DLPFC) for depression treatment. Two common targeting methods are the Beam F3 method and the 5.5 cm rule. OBJECTIVE: Evaluate the anatomical reliability of technician-identified DLPFC targets and obtain consensus average brain and scalp MNI152 coordinates. METHODS: Three trained TMS technicians performed repeated targeting using both the Beam F3 method and 5.5 cm rule in ten healthy subjects (n = 162). Average target locations were plotted on 7T structural MRIs to compare inter- and intra-rater reliability, respectively. RESULTS: (1) Beam F3 inter- and intra-rater reliability was superior to 5.5 cm targeting (p = 0.0005 and 0.0035). (2) The average Beam F3 location was 2.6±1.0 cm anterolateral to the 5.5 cm method. CONCLUSIONS: Beam F3 targeting demonstrates greater precision and reliability than the 5.5 cm method and identifies a different anatomical target.

A new device to improve target localization for transcranial magnetic stimulation therapy.

BACKGROUND: Accurate identification of cranial midline structures is essential for many targeting techniques that use repetitive transcranial magnetic stimulation (rTMS), including the Beam F3 method used for depression treatment. OBJECTIVE: Evaluate whether a novel, laser-sighted device will assist with more accurate identification of the cranial midline relative to standard scalp-based measurement procedures. METHODS: Three trained TMS technicians performed repeated scalp-based measurements to identify the inion and vertex on five subjects (n = 54 measurements). Measurements were compared to points identified with the midline localizer device and the true midline as defined by MRI midline structures. RESULTS: Use of the midline localizer was more accurate for midline identification than technician measurement (p = 0.00025) and the ratio of localizing the midline within 5 mm was higher (78% versus 54%, p = 0.008). CONCLUSION: Use of a laser-sighted midline localizer device can improve the accuracy of scalp measurements associated with target localization for rTMS treatment protocols.

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.

REM sleep twitches rouse nascent cerebellar circuits: Implications for sensorimotor development.

The cerebellum is critical for sensorimotor integration and undergoes extensive postnatal development. During the first postnatal week in rats, climbing fibers polyinnervate Purkinje cells and, before granule cell migration, mossy fibers make transient, direct connections with Purkinje cells. Activity-dependent processes are assumed to play a critical role in the development and refinement of these and other aspects of cerebellar circuitry. However, the sources and patterning of activity have not been described. We hypothesize that sensory feedback (i.e., reafference) from myoclonic twitches in sleeping newborn rats is a prominent driver of activity for the developing cerebellum. Here, in 6-day-old rats, we show that Purkinje cells exhibit substantial state-dependent changes in complex and simple spike activity-primarily during active sleep. In addition, this activity increases significantly during bouts of twitching. Moreover, the surprising observation of twitch-dependent increases in simple spike activity at this age suggests a functional engagement of mossy fibers before the parallel fiber system has developed. Based on these and other results, we propose that twitching comprises a unique class of self-produced movement that drives critical aspects of activity-dependent development in the cerebellum and other sensorimotor systems.

Rapid whisker movements in sleeping newborn rats.

Spontaneous activity in the sensory periphery drives infant brain activity and is thought to contribute to the formation of retinotopic and somatotopic maps. In infant rats during active (or REM) sleep, brainstem-generated spontaneous activity triggers hundreds of thousands of skeletal muscle twitches each day; sensory feedback from the resulting limb movements is a primary activator of forebrain activity. The rodent whisker system, with its precise isomorphic mapping of individual whiskers to discrete brain areas, has been a key contributor to our understanding of somatotopic maps and developmental plasticity. But although whisker movements are controlled by dedicated skeletal muscles, spontaneous whisker activity has not been entertained as a contributing factor to the development of this system. Here we report in 3- to 6-day-old rats that whiskers twitch rapidly and asynchronously during active sleep; furthermore, neurons in whisker thalamus exhibit bursts of activity that are tightly associated with twitches but occur infrequently during waking. Finally, we observed barrel-specific cortical activity during periods of twitching. This is the first report of self-generated, sleep-related twitches in the developing whisker system, a sensorimotor system that is unique for the precision with which it can be experimentally manipulated. The discovery of whisker twitching will allow us to attain a better understanding of the contributions of peripheral sensory activity to somatosensory integration and plasticity in the developing nervous system.