Intact Auditory Cortical Cross-Frequency Coupling in Early and Chronic Schizophrenia.

BACKGROUND: Previous work has identified a hierarchical organization of neural oscillations that supports performance of complex cognitive and perceptual tasks, and can be indexed with phase-amplitude coupling (PAC) between low- and high-frequency oscillations. Our aim was to employ enhanced source localization afforded by magnetoencephalography (MEG) to expand on earlier reports of intact auditory cortical PAC in schizophrenia and to investigate how PAC may evolve over the early and chronic phases of the illness. METHODS: Individuals with early schizophrenia (n=12) (≤5 years of illness duration), chronic schizophrenia (n=16) (>5 years of illness duration) and healthy comparators (n = 17) performed the auditory steady state response (ASSR) to 40, 30, and 20 Hz stimuli during MEG recordings. We estimated amplitude and PAC on the MEG ASSR source localized to the auditory cortices. RESULTS: Gamma amplitude during 40-Hz ASSR exhibited a significant group by hemisphere interaction, with both patient groups showing reduced right hemisphere amplitude and no overall lateralization in contrast to the right hemisphere lateralization demonstrated in controls. We found significant PAC in the right auditory cortex during the 40-Hz entrainment condition relative to baseline, however, PAC did not differ significantly between groups. CONCLUSIONS: In the current study, we demonstrated an apparent sparing of ASSR-related PAC across phases of the illness, in contrast with impaired cortical gamma oscillation amplitudes. The distinction between our PAC and evoked ASSR findings supports the notion of separate but interacting circuits for the generation and maintenance of sensory gamma oscillations. The apparent sparing of PAC in both early and chronic schizophrenia patients could imply that the neuropathology of schizophrenia differentially affects these mechanisms across different stages of the disease. Future studies should investigate the distinction between PAC during passive tasks and more cognitively demanding task such as working memory so that we can begin to understand the influence of schizophrenia neuropathology on the larger framework for modulating neurocomputational capacity.

Pitch and Duration Mismatch Negativity and Premorbid Intellect in the First Hospitalized Schizophrenia Spectrum.

Mismatch negativity (MMN) is a robustly abnormal brainwave in chronically ill schizophrenia that has generated interest as a disease presence biomarker. Reports of MMN reduction in first-episode schizophrenia have been equivocal, raising uncertainty about its reduction at first psychotic break. Here we tested 29 schizophrenia-spectrum participants under 1 year from their first hospitalization for psychosis and 40 age-, gender-, parental socioeconomic status-, and Wechsler Adult Intelligence Scales III Information-matched healthy controls on both pitch and duration MMN. Participants performed a visual checkerboard tracking task while standard (1kHz, 50ms, 80%), pitch-deviant (1.2kHz, 50ms, 10%) and duration-deviant (1kHz, 100ms, 10%) tones were presented over headphones (75 dB) and EEG was recorded. Independent component analysis was used to remove eye movements and visual stimulus processing activity. Groups did not differ in pitch MMN or duration MMN amplitudes. Smaller pitch and duration MMN amplitudes were associated with lower estimates of premorbid intellect in all participants and independently with greater positive symptoms in first hospitalized schizophrenia. Overall MMN reduction was not present in these relatively high functioning individuals at the first episode of schizophrenia, and therefore is not a good disease presence biomarker for this sample. Future research is warranted to determine the degree of MMN reduction at the first episode of psychosis across a greater range of cognitive impairment, the utility of MMN as an indicator of risk or diagnosis, and its role for understanding pathophysiological mechanisms in emerging psychosis.

Development of sensory gamma oscillations and cross-frequency coupling from childhood to early adulthood.

Given the importance of gamma oscillations in normal and disturbed cognition, there has been growing interest in their developmental trajectory. In the current study, age-related changes in sensory cortical gamma were studied using the auditory steady-state response (ASSR), indexing cortical activity entrained to a periodic auditory stimulus. A large sample (n = 188) aged 8-22 years had electroencephalography recording of ASSR during 20-, 30-, and 40-Hz click trains, analyzed for evoked amplitude, phase-locking factor (PLF) and cross-frequency coupling (CFC) with lower frequency oscillations. Both 40-Hz evoked power and PLF increased monotonically from 8 through 16 years, and subsequently decreased toward ages 20-22 years. CFC followed a similar pattern, with strongest age-related modulation of 40-Hz amplitude by the phase of delta oscillations. In contrast, the evoked power, PLF and CFC for the 20- and 30-Hz stimulation were distinct from the 40-Hz condition, with flat or decreasing profiles from childhood to early adulthood. The inverted U-shaped developmental trajectory of gamma oscillations may be consistent with interacting maturational processes-such as increasing fast GABA inhibition that enhances gamma activity and synaptic pruning that decreases gamma activity-that may continue from childhood through to adulthood.

Cortico-Cortical Connectivity between Right Parietal and Bilateral Primary Motor Cortices during Imagined and Observed Actions: A Combined TMS/tDCS Study.

Previous transcranial magnetic stimulation (TMS) studies showed functional connections between the parietal cortex (PC) and the primary motor cortex (M1) during tasks of different reaching-to-grasp movements. Here, we tested whether the same network is involved in cognitive processes such as imagined or observed actions. Single pulse TMS of the right and left M1 during rest and during a motor imagery and an action observation task (i.e., an index-thumb pinch grip in both cases) was used to measure corticospinal excitability changes before and after conditioning of the right PC by 10 min of cathodal, anodal, or sham transcranial direct current stimulation (tDCS). Corticospinal excitability was indexed by the size of motor-evoked potentials (MEPs) from the contralateral first dorsal interosseous (FDI; target) and abductor digiti minimi muscle (control) muscles. Results showed selective ipsilateral effects on the M1 excitability, exclusively for motor imagery processes: anodal tDCS enhanced the MEPs' size from the FDI muscle, whereas cathodal tDCS decreased it. Only cathodal tDCS impacted corticospinal facilitation induced by action observation. Sham stimulation was always uneffective. These results suggest that motor imagery, differently from action observation, is sustained by a strictly ipsilateral parieto-motor cortex circuits. Results might have implication for neuromodulatory rehabilitative purposes.

Temporal dynamics of memory trace formation in the human prefrontal cortex.

Event-related repetitive transcranial magnetic stimulation (rTMS) can dynamically interfere with the memory encoding of complex visual scenes. Here, we investigated the critical time elapsing from stimulus presentation to the formation of an effective memory trace by delivering rTMS (900 ms at 20 Hz) during the encoding of visual scenes at different poststimulus delays (from 100 to 500 ms) in 28 healthy volunteers. The stimulation delay showed a robust inverse correlation with the correct retrieval of encoded images. In particular, rTMS stimulation delivered with a delay of 500 ms and lasting for 400 ms after stimulus offset resulted in a huge drop in retrieval accuracy. Such a timing suggests that rTMS affects the formation of long-term memory through interference with postperceptual executive processes, rather than with perceptual analysis of the stimuli. The effect was specific for stimulation of the left dorsolateral prefrontal cortex (DLPFC), whereas rTMS applied to the right DLPFC, vertex (active control site), as well as sham stimulation (placebo) did not affect accuracy. These results confirm the crucial role of the left DLPFC in encoding and provide novel information about the critical timing of its engagement in the formation, consolidation, and maintenance of the memory trace.

Event-related rTMS at encoding affects differently deep and shallow memory traces.

The "level of processing" effect is a classical finding of the experimental psychology of memory. Actually, the depth of information processing at encoding predicts the accuracy of the subsequent episodic memory performance. When the incoming stimuli are analyzed in terms of their meaning (semantic, or deep, encoding), the memory performance is superior with respect to the case in which the same stimuli are analyzed in terms of their perceptual features (shallow encoding). As suggested by previous neuroimaging studies and by some preliminary findings with transcranial magnetic stimulation (TMS), the left prefrontal cortex may play a role in semantic processing requiring the allocation of working memory resources. However, it still remains unclear whether deep and shallow encoding share or not the same cortical networks, as well as how these networks contribute to the "level of processing" effect. To investigate the brain areas casually involved in this phenomenon, we applied event-related repetitive TMS (rTMS) during deep (semantic) and shallow (perceptual) encoding of words. Retrieval was subsequently tested without rTMS interference. RTMS applied to the left dorsolateral prefrontal cortex (DLPFC) abolished the beneficial effect of deep encoding on memory performance, both in terms of accuracy (decrease) and reaction times (increase). Neither accuracy nor reaction times were instead affected by rTMS to the right DLPFC or to an additional control site excluded by the memory process (vertex). The fact that online measures of semantic processing at encoding were unaffected suggests that the detrimental effect on memory performance for semantically encoded items took place in the subsequent consolidation phase. These results highlight the specific causal role of the left DLPFC among the wide left-lateralized cortical network engaged by long-term memory, suggesting that it probably represents a crucial node responsible for the improved memory performance induced by semantic processing.

Dysfunctions of cortical excitability in drug-naïve posttraumatic stress disorder patients.

BACKGROUND: The investigation of a wide set of transcranial magnetic stimulation (TMS)-related variables in both hemispheres might help to identify a pattern of cortical excitability changes in posttraumatic stress disorder (PTSD) patients, reflecting gamma-amino-butiric acid (GABA)/glutamate balance and dysfunction, and to determine whether some of these variables are related to clinical features. METHODS: In 20 drug-naive PTSD patients without comorbidity and 16 matched healthy control subjects we tested bilaterally with standard TMS procedures: resting motor threshold (RMT) to single-pulse TMS (reflecting ion channel function), paired-pulse short-latency intracortical inhibition (SICI; mainly reflecting GABA(A) function) and intracortical facilitation (ICF; mainly reflecting glutamatergic function), single-pulse cortical silent period (CSP; mainly reflecting GABA(B)-ergic function), and paired-pulse short-latency afferent inhibition (SAI; reflecting cholinergic mechanisms and their presynaptic GABA(A)-mediated modulation). RESULTS: The PTSD patients showed widespread impairment of GABA(A)-ergic SICI, which was reversed toward facilitation in both hemispheres in one-half of the patients, marked increase of glutamatergic ICF in the right hemisphere, and right-sided impairment of SAI. Illness duration and avoidance symptoms but not anxiety correlated with right-lateralized dysfunctions of cortical excitability. CONCLUSIONS: Although the neurobiological complexity of each TMS variable makes current results theoretical, the pattern of cortical excitability accompanying PTSD symptoms suggests a bilateral decrease of the GABA(A)-ergic function. This prevails in the right hemisphere, in association with a relative prevalence of the glutamatergic tone, a new finding that current neuroimaging investigations cannot provide due to the lack of reliable glutamate tracers. Results might help to disclose new pathophysiological aspects of PTSD symptoms, providing a rationale for future neuromodulatory strategies of treatment.