Massihullah Hamidi

Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes

BACKGROUND A previous study reported reductions in glial density and glia/neuron ratio in the amygdala of individuals with major depressive disorder (MDD), without a change in neuronal density. It is not known, however, whether this glial loss is due to astrocytes, oligodendrocytes, or microglia. METHODS Tissue samples, equally from the right and left hemispheres, were obtained from subjects diagnosed with MDD (n = 8), bipolar disorder (BD) (n = 9), or no psychiatric disorders (n = 10). Sections were stained immunohistochemically for S-100beta (for astrocytes) and human leukocyte antigen (for microglia), and with the Nissl method. In Nissl-stained sections, oligodendrocytes have more compact, darker-stained nuclei, whereas astrocytes and microglia have larger, lighter-stained nuclei, with more granular chromatin. Neurons are larger, with a nucleolus and stained cytoplasm. The density of glia was determined with stereologic methods. RESULTS The density of total glia and oligodendrocytes in the amygdala was significantly lower in MDD than in control subjects, but not significantly lower in BD compared with control subjects. The decreases were largely accounted for by differences in the left hemisphere. There was no significant decrease in astrocyte or microglia density in MDD or BD subjects. CONCLUSIONS The glial cell reduction previously found in the amygdala in MDD is primarily due to oligodendrocytes.

Repetitive Transcranial Magnetic Stimulation Dissociates Working Memory Manipulation from Retention Functions in the Prefrontal, but not Posterior Parietal, Cortex

Understanding the contributions of the prefrontal cortex (PFC) to working memory is central to understanding the neural bases of high-level cognition. One question that remains controversial is whether the same areas of the dorsolateral PFC (dlPFC) that participate in the manipulation of information in working memory also contribute to its short-term retention (STR). We evaluated this question by first identifying, with functional magnetic resonance imaging (fMRI), brain areas involved in manipulation. Next, these areas were targeted with repetitive transcranial magnetic stimulation (rTMS) while subjects performed tasks requiring only the STR or the STR plus manipulation of information in working memory. fMRI indicated that manipulation-related activity was independent of retention-related activity in both the PFC and superior parietal lobule (SPL). rTMS, however, yielded a different pattern of results. Although rTMS of the dlPFC selectively disrupted manipulation, rTMS of the SPL disrupted manipulation and STR to the same extent. rTMS of the postcentral gyrus (a control region) had no effect on performance. The implications of these results are twofold. In the PFC, they are consistent with the view that this region contributes more importantly to the control of information in working memory than to its STR. In the SPL, they illustrate the importance of supplementing the fundamentally correlational data from neuroimaging with a disruptive method, which affords stronger inference about structure-function relations.

A common neural substrate for language production and verbal working memory

Verbal working memory (VWM), the ability to maintain and manipulate representations of speech sounds over short periods, is held by some influential models to be independent from the systems responsible for language production and comprehension [e.g., Baddeley, A. D. Working memory, thought, and action. New York, NY: Oxford University Press, 2007]. We explore the alternative hypothesis that maintenance in VWM is subserved by temporary activation of the language production system [Acheson, D. J., & MacDonald, M. C. Verbal working memory and language production: Common approaches to the serial ordering of verbal information. Psychological Bulletin, 135, 50–68, 2009b]. Specifically, we hypothesized that for stimuli lacking a semantic representation (e.g., nonwords such as mun), maintenance in VWM can be achieved by cycling information back and forth between the stages of phonological encoding and articulatory planning. First, fMRI was used to identify regions associated with two different stages of language production planning: the posterior superior temporal gyrus (pSTG) for phonological encoding (critical for VWM of nonwords) and the middle temporal gyrus (MTG) for lexical–semantic retrieval (not critical for VWM of nonwords). Next, in the same subjects, these regions were targeted with repetitive transcranial magnetic stimulation (rTMS) during language production and VWM task performance. Results showed that rTMS to the pSTG, but not the MTG, increased error rates on paced reading (a language production task) and on delayed serial recall of nonwords (a test of VWM). Performance on a lexical–semantic retrieval task (picture naming), in contrast, was significantly sensitive to rTMS of the MTG. Because rTMS was guided by language production-related activity, these results provide the first causal evidence that maintenance in VWM directly depends on the long-term representations and processes used in speech production.

Repetitive Transcranial Magnetic Stimulation Affects behavior by Biasing Endogenous Cortical Oscillations

A governing assumption about repetitive transcranial magnetic stimulation (rTMS) has been that it interferes with task-related neuronal activity – in effect, by “injecting noise” into the brain – and thereby disrupts behavior. Recent reports of rTMS-produced behavioral enhancement, however, call this assumption into question. We investigated the neurophysiological effects of rTMS delivered during the delay period of a visual working memory task by simultaneously recording brain activity with electroencephalography (EEG). Subjects performed visual working memory for locations or for shapes, and in half the trials a 10-Hz train of rTMS was delivered to the superior parietal lobule (SPL) or a control brain area. The wide range of individual differences in the effects of rTMS on task accuracy, from improvement to impairment, was predicted by individual differences in the effect of rTMS on power in the alpha-band of the EEG (∼10 Hz): a decrease in alpha-band power corresponded to improved performance, whereas an increase in alpha-band power corresponded to the opposite. The EEG effect was localized to cortical sources encompassing the frontal eye fields and the intraparietal sulcus, and was specific to task (location, but not object memory) and to rTMS target (SPL, not control area). Furthermore, for the same task condition, rTMS-induced changes in cross-frequency phase synchrony between alpha- and gamma-band (>40 Hz) oscillations predicted changes in behavior. These results suggest that alpha-band oscillations play an active role cognitive processes and do not simply reflect absence of processing. Furthermore, this study shows that the complex effects of rTMS on behavior can result from biasing endogenous patterns of network-level oscillations.

Evaluating frontal and parietal contributions to spatial working memory with repetitive transcranial magnetic stimulation.

Functional neuroimaging studies have produced contradictory data about the extent to which specific regions of the frontal and the posterior parietal cortices contribute to the retention of information in spatial working memory. We used high frequency repetitive transcranial magnetic stimulation (rTMS) to assess the necessity for the short-term retention of spatial information of brain areas identified by previous functional imaging studies: dorsolateral prefrontal cortex (dlPFC), frontal eye fields (FEF), superior parietal lobule (SPL) and intraparietal sulcus (IPS). 10 Hz rTMS spanned the 3-s delay period of a spatial delayed-recognition task. The postcentral gyrus (PCG) was included to control for any regionally non-specific effects of rTMS. The only regionally-specific effect was a significant decrease in reaction time when rTMS was applied to SPL. Additionally, rTMS lowered accuracy to a greater extent when applied to left than to right hemisphere, and was more disruptive when applied contralaterally vs. ipsilaterally to the visual field in which the memory probe was presented. Although seemingly paradoxical, the finding of rTMS-induced improvement in task performance has a precedent, and is consistent with the idea that regions associated with spatial sensory-motor processing make necessary contributions to the short-term retention of this information. Possible factors underlying rTMS-induced behavioral facilitation are considered.

Evaluating the role of prefrontal and parietal cortices in memory-guided response with repetitive transcranial magnetic stimulation.

The dorsolateral prefrontal cortex (dlPFC) plays an important role in working memory, including the control of memory-guided response. In this study, with 24 subjects, we used high frequency repetitive transcranial magnetic stimulation (rTMS) to evaluate the role of the dlPFC in memory-guided response to two different types of spatial working memory tasks: one requiring a recognition decision about a probe stimulus (operationalized with a yes/no button press), another requiring direct recall of the memory stimulus by moving a cursor to the remembered location. In half the trials, randomly distributed, rTMS was applied to the dlPFC and in a separate session, the superior parietal lobule (SPL), a brain area implicated in spatial working memory storage. A 10-Hz (3s, 110% of motor threshold) train of TMS was delivered at the onset of the response period. We found that only dlPFC rTMS significantly affected performance, with rTMS of right dlPFC decreasing accuracy on delayed-recall trials, and rTMS of left and right dlPFC decreasing and enhancing accuracy, respectively, on delayed-recognition trials. These findings confirm that the dlPFC plays an important role in memory-guided response, and suggest that the nature of this role varies depending on the processes required for making a response.

Brain responses evoked by high-frequency repetitive transcranial magnetic stimulation: An event-related potential study

BACKGROUND Many recent studies have used repetitive transcranial magnetic stimulation (rTMS) to study brain-behavior relationships. However, the pulse-to-pulse neural effects of rapid delivery of multiple TMS pulses are unknown largely because of TMS-evoked electrical artifacts limiting recording of brain activity.ObjectiveIn this study, TMS-related artifacts were removed with independent component analysis (ICA), which allowed for the investigation of the neurophysiologic effects of rTMS with simultaneous electroencephalographic (EEG) recordings. METHODS Repetitive TMS trains of 10 Hz, 3 seconds (110% of motor threshold) were delivered to the postcentral gyrus and superior parietal lobule in 16 young adults. Simultaneous EEG recordings were made with a TMS-compatible system. The stereotypical pattern of TMS-related electrical artifacts was identified by ICA. RESULTS Removal of artifacts allowed for identification of a series of five evoked brain potentials occurring within 100 milliseconds of each TMS pulse. With the exception of the first potential, for both areas targeted, there was a quadratic relationship between potential peak amplitude and pulse number within the TMS train. This was characterized by a decrease, followed by a rise in amplitude. CONCLUSIONS ICA is an effective method for removal of TMS-evoked electrical artifacts in EEG data. With the use of this procedure we found that the physiologic responses to TMS pulses delivered in a high-frequency train of pulses are not independent. The sensitivity of the magnitude of these responses to recent stimulation history suggests a complex recruitment of multiple neuronal events with different temporal dynamics.

Does High-Frequency Repetitive Transcranial Magnetic Stimulation Produce Residual and/or Cumulative Effects Within an Experimental Session?

A common procedure for studying the effects on cognition of repetitive transcranial magnetic stimulation (rTMS) is to deliver rTMS concurrent with task performance, and to compare task performance on these trials versus on trials without rTMS. Recent evidence that TMS can have effects on neural activity that persist longer than the experimental session itself, however, raise questions about the assumption of the transient nature of rTMS that underlies many concurrent (or “online”) rTMS designs. To our knowledge, there have been no studies in the cognitive domain examining whether the application of brief trains of rTMS during specific epochs of a complex task may have effects that spill over into subsequent task epochs, and perhaps into subsequent trials. We looked for possible immediate spill-over and longer-term cumulative effects of rTMS in data from two studies of visual short-term delayed recognition. In 54 subjects, 10-Hz rTMS trains were applied to five different brain regions during the 3-s delay period of a spatial task, and in a second group of 15 subjects, electroencephalography (EEG) was recorded while 10-Hz rTMS was applied to two brain areas during the 3-s delay period of both spatial and object tasks. No evidence for immediate effects was found in the comparison of the memory probe-evoked response on trials that were vs. were not preceded by delay-period rTMS. No evidence for cumulative effects was found in analyses of behavioral performance, and of EEG signal, as a function of task block. The implications of these findings, and their relation to the broader literature on acute vs. long-lasting effects of rTMS, are considered.