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Septo-hippocampal GABAergic neurons immunoreactive for parvalbumin are thought to play a crucial role in the generation of hippocampal theta oscillations associated with a specific stage of memory formation. Here we use in vivo juxtacellular recording and filling in the medial septum followed by immunocytochemical identification of the recorded cells containing parvalbumin to determine their firing pattern, phase relationship with hippocampal theta, morphology, and to thereby reveal their involvement in the generation of hippocampal theta activity. We have demonstrated that GABAergic medial septal neurons form two distinct populations exhibiting highly regular bursting activity that is tightly coupled to either the trough (178°) or the peak (330°) of hippocampal theta waves. Additionally, different types of bursting as well as nonbursting activity patterns were also observed. The morphological reconstruction of theta-bursting neurons revealed extensive axon arbors of these cells with numerous local collaterals establishing symmetrical synapses; thus, synchrony among the septal pacemaker units may be brought about by their recurrent collateral interactions. Long projecting axons could also be found running dorsally toward the hippocampus and ventrally in the direction of basal forebrain regions. We conclude that GABAergic neurons in the medial septum, which are known to selectively innervate hippocampal interneurons, are in a position to induce rhythmic disinhibition in the hippocampus and other theta-related subcortical areas at two different phases of hippocampal theta.

Brain electrical activity is largely composed of oscillations at characteristic frequencies. These rhythms are hierarchically organized and are thought to perform important pathological and physiological functions. The slow wave is a fundamental cortical rhythm that emerges in deep non-rapid eye movement sleep. In animals, the slow wave modulates delta, theta, spindle, alpha, beta, gamma and ripple oscillations, thus orchestrating brain electrical rhythms in sleep. While slow wave activity can enhance epileptic manifestations, it is also thought to underlie essential restorative processes and facilitate the consolidation of declarative memories. Animal studies show that slow wave activity is composed of rhythmically recurring phases of widespread, increased cortical cellular and synaptic activity, referred to as active- or up-state, followed by cellular and synaptic inactivation, referred to as silent- or down-state. However, its neural mechanisms in humans are poorly understood, since the traditional intracellular techniques used in animals are inappropriate for investigating the cellular and synaptic/transmembrane events in humans. To elucidate the intracortical neuronal mechanisms of slow wave activity in humans, novel, laminar multichannel microelectrodes were chronically implanted into the cortex of patients with drug-resistant focal epilepsy undergoing cortical mapping for seizure focus localization. Intracortical laminar local field potential gradient, multiple-unit and single-unit activities were recorded during slow wave sleep, related to simultaneous electrocorticography, and analysed with current source density and spectral methods. We found that slow wave activity in humans reflects a rhythmic oscillation between widespread cortical activation and silence. Cortical activation was demonstrated as increased wideband (0.3-200 Hz) spectral power including virtually all bands of cortical oscillations, increased multiple- and single-unit activity and powerful inward transmembrane currents, mainly localized to the supragranular layers. Neuronal firing in the up-state was sparse and the average discharge rate of single cells was less than expected from animal studies. Action potentials at up-state onset were synchronized within +/-10 ms across all cortical layers, suggesting that any layer could initiate firing at up-state onset. These findings provide strong direct experimental evidence that slow wave activity in humans is characterized by hyperpolarizing currents associated with suppressed cell firing, alternating with high levels of oscillatory synaptic/transmembrane activity associated with increased cell firing. Our results emphasize the major involvement of supragranular layers in the genesis of slow wave activity.

The alpha rhythm is the longest-studied brain oscillation and has been theorized to play a key role in cognition. Still, its physiology is poorly understood. In this study, we used microelectrodes and macroelectrodes in surgical epilepsy patients to measure the intracortical and thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in both visual and somatosensory cortex propagates from higher-order to lower-order areas. In posterior cortex, alpha propagates from higher-order anterosuperior areas toward the occipital pole, whereas alpha in somatosensory cortex propagates from associative regions toward primary cortex. Several analyses suggest that this cortical alpha leads pulvinar alpha, complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortical layers. Together, these results suggest that the alpha rhythm likely reflects short-range supragranular feedback, which propagates from higher- to lower-order cortex and cortex to thalamus. These physiological insights suggest how alpha could mediate feedback throughout the thalamocortical system.

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The alpha rhythm is the longest studied brain oscillation and has been theorized to 28 play a key role in cognition. Still, its physiology is poorly understood. In this study, we used 29 micro and macro electrodes in surgical epilepsy patients to measure the intracortical and 30 thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in 31 posterior cortex propagates from higher-order anterosuperior areas towards the occipital pole, 32 consistent with alpha effecting top-down processing. This cortical alpha leads pulvinar alpha, 33 complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by 34 currents and firing in supragranular cortical layers. Together, these results suggest that the alpha 35 2 rhythm likely reflects short-range supragranular feedback which propagates from higher to 36 lower-order cortex and cortex to thalamus. These physiological insights suggest how alpha could 37 mediate feedback throughout the thalamocortical system. 38Main Text: Alpha oscillations (7-13 Hz) 1 are the most salient EEG event during wakefulness 39 and may be fundamental for top-down cognitive processes 2,3 such as attention 4 , perception 5,6 , 40 functional inhibition 7 and working memory 8 . However, the underlying neural structure(s) and 41 circuits which generate alpha are intensely controversial. Studies have pointed to the thalamus as 42 the primary alpha pacemaker, with the classic posterior alpha rhythm driven by the pulvinar 43 and/or lateral geniculate nucleus (LGN) 4,[9][10][11] . Within the cortex, it's widely assumed that alpha 44 originates from infragranular layers driven by layer V pyramidal cells [12][13][14][15][16] . Despite the 45 prevalence of these hypotheses, the studies used to support them are not definitive; previous 46 electrophysiological literature have either used a distant reference susceptible to volume 47 conduction 4,12,14 , were performed in vitro 13 or relied on extracranial recordings 17 (see 48 Discussion). Crucially, none of these hypotheses have been directly tested via invasive 49 recordings in humans. We therefore analyzed focal micro and macro electrode recordings from 50 human neocortex and thalamus in surgical epilepsy patients to characterize alpha's generation 51 during quiet wakefulness.52 53 3We analyzed electrocorticography (ECoG) recordings of spontaneous alpha oscillations 54 (4.54±.87 minutes, mean ± standard deviation) in the occipital, posterior temporal, and parietal 55 cortices of 5 patients (3 of whom performed an eye closure task) ( Supplementary Fig. 1, 56 Supplementary Table 1) (ECoG Patients E1-5). Strikingly, alpha oscillations propagated as 57travelling waves from anterosuperior cortex towards posteroinferior areas ( Fig. 1-2, 58 Supplementary Fig. 4) 18 . To quantify this propagation, we used a two-pass third-order zero-59 phase shift Butterworth Filter between 7-13 Hz to extract alpha-band activity. The Hilbert 60Transform was then applied to find both the amplitude and phase of ongoing alpha...

Improvements in European epilepsy surgery over time are modest but significant, including higher surgical volume, shorter disease duration, and improved postsurgical seizure outcomes. Early referral for evaluation is required to continue on this encouraging trend.

The role of cortical connectivity in brain function and pathology is increasingly being recognized. While in vivo magnetic resonance imaging studies have provided important insights into anatomical and functional connectivity, these methodologies are limited in their ability to detect electrophysiological activity and the causal relationships that underlie effective connectivity. Here, we describe results of cortico-cortical evoked potential (CCEP) mapping using single pulse electrical stimulation in 25 patients undergoing seizure monitoring with subdural electrode arrays. Mapping was performed by stimulating adjacent electrode pairs and recording CCEPs from the remainder of the electrode array. CCEPs reliably revealed functional networks and showed an inverse relationship to distance between sites. Coregistration to Brodmann areas (BA) permitted group analysis. Connections were frequently directional with 43% of early responses and 50% of late responses of connections reflecting relative dominance of incoming or outgoing connections. The most consistent connections were seen as outgoing from motor cortex, BA6–BA9, somatosensory (SS) cortex, anterior cingulate cortex, and Broca's area. Network topology revealed motor, SS, and premotor cortices along with BA9 and BA10 and language areas to serve as hubs for cortical connections. BA20 and BA39 demonstrated the most consistent dominance of outdegree connections, while BA5, BA7, auditory cortex, and anterior cingulum demonstrated relatively greater indegree. This multicenter, large-scale, directional study of local and long-range cortical connectivity using direct recordings from awake, humans will aid the interpretation of noninvasive functional connectome studies.