Ali Mazaheri

Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder

Little is known about the underlying neural mechanism of deep brain stimulation (DBS). We found that DBS targeted at the nucleus accumbens (NAc) normalized NAc activity, reduced excessive connectivity between the NAc and prefrontal cortex, and decreased frontal low-frequency oscillations during symptom provocation in patients with obsessive-compulsive disorder. Our findings suggest that DBS is able to reduce maladaptive activity and connectivity of the stimulated region.

Asymmetric Amplitude Modulations of Brain Oscillations Generate Slow Evoked Responses

Electrophysiological data measured by electroencephalography and magnetoencephalography (MEG) are widely used to investigate human brain activity in various cognitive tasks. This is typically done by characterizing event-related potentials/fields or modulations of oscillatory activity (e.g., event-related synchronization) in response to cognitively relevant stimuli. Here, we provide a link between the two phenomena. An essential component of our theory is that peaks and troughs of oscillatory activity fluctuate asymmetrically; e.g., peaks are more strongly modulated than troughs in response to stimuli. As a consequence, oscillatory brain activity will not “average out” when multiple trials are averaged. Using MEG, we demonstrate that such asymmetric amplitude fluctuations of the oscillatory alpha rhythm explain the generation of slow event-related fields. Furthermore, we provide a physiological explanation for the observed asymmetric amplitude fluctuations. In particular, slow event-related components are modulated by a wide range of cognitive tasks. Hence, our findings provide new insight into the physiological basis of cognitive modulation in event-related brain activity.

Deep brain stimulation in addiction: a review of potential brain targets

Deep brain stimulation (DBS) is an adjustable, reversible, non-destructive neurosurgical intervention using implanted electrodes to deliver electrical pulses to areas in the brain. DBS is currently investigated in psychiatry for the treatment of refractory obsessive–compulsive disorder, Tourette syndrome and depressive disorder. Although recent research in both animals and humans has indicated that DBS may be an effective intervention for patients with treatment-refractory addiction, it is not yet entirely clear which brain areas should be targeted. The objective of this review is to provide a systematic overview of the published literature on DBS and addiction and outline the most promising target areas using efficacy and adverse event data from both preclinical and clinical studies. We found 7 animal studies targeting six different brain areas: nucleus accumbens (NAc), subthalamic nucleus (STN), dorsal striatum, lateral habenula, medial prefrontal cortex (mPFC) and hypothalamus, and 11 human studies targeting two different target areas: NAc and STN. Our analysis of the literature suggests that the NAc is currently the most promising DBS target area for patients with treatment-refractory addiction. The mPFC is another promising target, but needs further exploration to establish its suitability for clinical purposes. We conclude the review with a discussion on translational issues in DBS research, medical ethical considerations and recommendations for clinical trials with DBS in patients with addiction.

Modulations in oscillatory activity with amplitude asymmetry can produce cognitively relevant event-related responses

Event-related responses and oscillatory activity are typically regarded as manifestations of different neural processes. Recent work has nevertheless revealed a mechanism by which slow event-related responses are created as a direct consequence of modulations in brain oscillations with nonsinusoidal properties. It remains unknown if this mechanism applies to cognitively relevant event-related responses. Here, we investigated whether sustained event-related fields (ERFs) measured during working memory maintenance can be explained by modulations in oscillatory power. In particular, we focused on contralateral delayed activity (CDA) typically observed in working memory tasks in which hemifield specific attention is manipulated. Using magnetoencephalography, we observed sustained posterior ERFs following the presentation of the memory target. These ERFs were systematically lateralized with respect to the hemisphere in which the target was presented. A strikingly similar pattern emerged for modulations in alpha (9–13 Hz) power. The alpha power and ERF lateralization were strongly correlated over subjects. Based on a mechanistic argument pertaining to the nonsinusoidal properties of the alpha activity, we conclude that the ERFs modulated by working memory are likely to be directly produced by the modulations in oscillatory alpha activity. Given that posterior alpha activity typically reflects disengagement, we conclude that the CDA is not attributable to an additive process reflecting memory maintenance per se but, rather, is a consequence of how attentional resources are allocated.

Rhythmic Pulsing: Linking Ongoing Brain Activity with Evoked Responses

The conventional assumption in human cognitive electrophysiology using EEG and MEG is that the presentation of a particular event such as visual or auditory stimuli evokes a “turning on” of additional brain activity that adds to the ongoing background activity. Averaging multiple event-locked trials is thought to result in the cancellation of the seemingly random phased ongoing activity while leaving the evoked response. However, recent work strongly challenges this conventional view and demonstrates that the ongoing activity is not averaged out due to specific non-sinusoidal properties. As a consquence, systematic modulations in ongoing activity can produce slow cortical evoked responses reflecting cognitive processing. In this review we introduce the concept of “rhythmic pulsing” to account for this specific non-sinusoidal property. We will explain how rhythmic pulsing can create slow evoked responses from a physiological perspective. We will also discuss how the notion of rhythmic pulsing provides a unifying framework linking ongoing oscillations, evoked responses and the brains capacity to process incoming information.

Modulation of Visually Evoked Cortical fMRI Responses by Phase of Ongoing Occipital Alpha Oscillations

Using simultaneous electroencephalography as a measure of ongoing activity and functional magnetic resonance imaging (fMRI) as a measure of the stimulus-driven neural response, we examined whether the amplitude and phase of occipital alpha oscillations at the onset of a brief visual stimulus affects the amplitude of the visually evoked fMRI response. When accounting for intrinsic coupling of alpha amplitude and occipital fMRI signal by modeling and subtracting pseudo-trials, no significant effect of prestimulus alpha amplitude on the evoked fMRI response could be demonstrated. Regarding the effect of alpha phase, we found that stimuli arriving at the peak of the alpha cycle yielded a lower blood oxygenation level-dependent (BOLD) fMRI response in early visual cortex (V1/V2) than stimuli presented at the trough of the cycle. Our results therefore show that phase of occipital alpha oscillations impacts the overall strength of a visually evoked response, as indexed by the BOLD signal. This observation complements existing evidence that alpha oscillations reflect periodic variations in cortical excitability and suggests that the phase of oscillations in postsynaptic potentials can serve as a mechanism of gain control for incoming neural activity. Finally, our findings provide a putative neural basis for observations of alpha phase dependence of visual perceptual performance.

Attention and temporal expectations modulate power, not phase, of ongoing alpha oscillations

The perception of near-threshold visual stimuli has been shown to depend in part on the phase (i.e., time in the cycle) of ongoing alpha (8–13 Hz) oscillations in the visual cortex relative to the onset of that stimulus. However, it is currently unknown whether the phase of the ongoing alpha activity can be manipulated by top–down factors such as attention or expectancy. Using three variants of a cross-modal attention paradigm with constant predictable stimulus onsets, we examined if cues signaling to attend to either the visual or the auditory domain influenced the phase of alpha oscillations in the associated sensory cortices. Importantly, intermixed in all three experiments, we included trials without a target to estimate the phase at target presentation without contamination from the early evoked responses. For these blank trials, at the time of expected target and distractor onset, we examined (1) the degree of the uniformity in phase angles across trials, (2) differences in phase angle uniformity compared with a pretarget baseline, and (3) phase angle differences between visual and auditory target conditions. Across all three experiments, we found that, although the cues induced a modulation in alpha power in occipital electrodes, neither the visual condition nor the auditory cue condition induced any significant phase-locking across trials during expected target or distractor presentation. These results suggest that, although alpha power can be modulated by top–down factors such as attention and expectation, the phase of the ongoing alpha oscillation is not under such control.

Differential Oscillatory Electroencephalogram Between Attention-Deficit/Hyperactivity Disorder Subtypes and Typically Developing Adolescents

BACKGROUND A neurobiological-based classification of attention-deficit/hyperactivity disorder (ADHD) subtypes has thus far remained elusive. The aim of this study was to use oscillatory changes in the electroencephalogram (EEG) related to informative cue processing, motor preparation, and top-down control to investigate neurophysiological differences between typically developing (TD) adolescents, and those diagnosed with predominantly inattentive (IA) or combined (CB) (associated with symptoms of inattention as well as impulsivity/hyperactivity) subtypes of ADHD. METHODS The EEG was recorded from 57 rigorously screened adolescents (12 to 17 years of age; 23 TD, 17 IA, and 17 CB), while they performed a cued flanker task. We examined the oscillatory changes in theta (3-5 Hz), alpha (8-12 Hz), and beta (22-25 Hz) EEG bands after cues that informed participants with which hand they would subsequently be required to respond. RESULTS Relative to TD adolescents, the IA group showed significantly less postcue alpha suppression, suggesting diminished processing of the cue in the visual cortex, whereas the CB group showed significantly less beta suppression at the electrode contralateral to the cued response hand, suggesting poor motor planning. Finally, both ADHD subtypes showed weak functional connectivity between frontal theta and posterior alpha, suggesting common top-down control impairment. CONCLUSIONS We found both distinct and common task-related neurophysiological impairments in ADHD subtypes. Our results suggest that task-induced changes in EEG oscillations provide an objective measure, which in conjunction with other sources of information might help distinguish between ADHD subtypes and therefore aid in diagnoses and evaluation of treatment.

Facilitation and inhibition in attention: Functional dissociation of pre-stimulus alpha activity, P1, and N1 components

Attention--the ability to attend to some things while ignoring others - can be best described as an emergent property of many neural mechanisms, facilitatory and inhibitory, working together to resolve competition for processing resources and control of behavior. Previous EEG and MEG studies examining the neural mechanisms underlying facilitation and inhibition of stimulus processing typically used paradigms requiring alternating shifts of attention in the spatial domain, with stimuli occurring at both attended and unattended locations. These studies generally observed greater pre-stimulus alpha oscillations over task-irrelevant vs. relevant posterior regions and bilateral attentional modulations of early sensory processing. In contrast, in the current series of experiments, participants continuously attended to only one hemifield and stimuli were only presented at the attended location, affording us an opportunity to elucidate the inhibitory and facilitatory effects of attention in the brain in a context in which spatial relevance was fixed. We found that continuous attention to one hemifield did not modulate prestimulus alpha activity in ipsilateral regions but did result in a perfectly lateralized P1 attention effect to ipsilateral posterior regions. Moreover, we found a bilateral N1 effect. These findings suggest that pre-stimulus alpha activity, the P1 and the N1 reflect qualitatively different aspects of attention; While pre-stimulus alpha-band activity may reflect a top-down inhibitory mechanism that critically depends on functional competition between task-relevant and irrelevant sensory regions, the ipsilateral P1 effect may reflect stimulus-triggered blocking of sensory processing in irrelevant networks, and the N1 effect facilitation of task-relevant processing.

Deep brain stimulation targeted at the nucleus accumbens decreases the potential for pathologic network communication.

D eep brain stimulation (DBS) entails electrode implantation and high-frequency electrical stimulation of a specific brain target. DBS targeted at the nucleus accumbens (NAc) is a promising treatment option for otherwise treatmentrefractory obsessive-compulsive disorder (OCD) (1). Recently, our group demonstrated that NAc DBS in OCD not only results in local activity changes but also in reduction of pathological overconnectivity throughout the frontostriatal network (2). This reduction in overconnectivity correlates with symptom improvements, empirically supporting the hypothesis that DBS overwrites pathologic network activity (3). The goal of our current endeavor was to determine mechanistically how DBS could modulate connectivity within the frontostriatal network. The electroencephalogram (EEG) is a noninvasive neuroimaging technique that provides a time window into the network activity of millions of neurons. Neuronal interactions in the EEG