The analysis of H.M.'s brain: A brief review of status and plans for future studies and tissue archive.

The famous amnesic patient Henry Molaison (H.M.) died on December 2, 2008. After extensive in situ magnetic resonance imaging in Boston, his brain was removed at autopsy and transported to the University of California San Diego. There the brain was prepared for frozen sectioning and cut into 2401, 70 µm coronal slices. While preliminary analyses of the brain sections have been reported, a comprehensive microscopic neuroanatomical analysis of the state of H.M.'s brain at the time of his death has not yet been published. The brain tissue and slides were subsequently moved to the University of California Davis and the slides digitized at high resolution. Initial stages of producing a website for the public viewing of the images were also carried out. Recently, the slides, digital images, and tissue have been transferred to Boston University for permanent archiving. A new steering committee has been established and plans are in place for completion of a freely accessible H.M. website. Research publications on the microscopic anatomy and neuropathology of H.M.'s brain at the time of his death are also planned. We write this commentary to provide the hippocampus and memory neuroscience communities with a brief summary of what has transpired following H.M.'s death and outline plans for future publications and a tissue archive.

Causal evidence supporting functional dissociation of verbal and spatial working memory in the human dorsolateral prefrontal cortex.

The human dorsolateral prefrontal cortex (dlPFC) is crucial for monitoring and manipulating information in working memory, but whether such contributions are domain-specific remains unsettled. Neuroimaging studies have shown bilateral dlPFC activity associated with working memory independent of the stimulus domain, but the causality of this relationship cannot be inferred. Repetitive transcranial magnetic stimulation (rTMS) has the potential to test whether the left and right dlPFC contribute equally to verbal and spatial domains; however, this is the first study to investigate the interaction of task domain and hemisphere using offline rTMS to temporarily modulate dlPFC activity. In separate sessions, 20 healthy right-handed adults received 1 Hz rTMS to the left dlPFC and right dlPFC, plus the vertex as a control site. The working memory performance was assessed pre-rTMS and post-rTMS using both verbal-'letter' and spatial-'location' versions of the 3-back task. The response times were faster post-rTMS, independent of the task domain or stimulation condition, indicating the influence of practice or other nonspecific effects. For accuracy, rTMS of the right dlPFC, but not the left dlPFC or vertex, led to a transient dissociation, reducing spatial, but increasing verbal accuracy. A post-hoc correlation analysis found no relationship between these changes, indicating that the substrates underlying the verbal and spatial domains are functionally independent. Collapsing across time, there was a trend towards a double dissociation, suggesting a potential laterality in the functional organisation of verbal and spatial working memory. At a minimum, these findings provide human evidence for domain-specific contributions of the dlPFC to working memory and reinforce the potential of rTMS to ameliorate cognition.

In vivo microdialysis shows differential effects of prenatal protein malnutrition and stress on norepinephrine, dopamine, and serotonin levels in rat orbital frontal cortex.

Prenatal protein malnutrition (PPM) alters the developing brain including changes in monoaminergic systems and attention. In the present study, we used in vivo microdialysis to examine the relationship between PPM, acute stress, and extracellular serotonin (5HT), dopamine (DA) and norepinephrine (NE) in both hemispheres of lateral orbital frontal cortices (lOFC) in the adult rat. We hypothesized that prenatal protein malnutrition would alter extracellular concentrations of cortical monoamines. The effects of an acute restraint stress were also assessed because PPM alters the brain's response to stress. We used adult male, Long-Evans rats [10 prenatally malnourished (6% casein) and 10 prenatally well-nourished (25% casein)]. Samples were collected from the left and right hemispheres of the lOFC every 20 min for 6 hr total and quantified using high-performance liquid chromatography (HPLC). After 2 hr of sampling, animals were exposed to a 40-min restraint stress. Extracellular levels of NE were significantly higher in PPM animals than in well-nourished controls across both hemispheres at all time-points. In contrast, baseline levels of 5HT and DA levels did not differ between nutritional groups. 5HT levels, but not NE or DA levels, were elevated compared to baseline levels in both nutritional groups and in both hemispheres during the first 20 min of stress exposure. These data highlight the impact of PPM on neuromodulatory systems and the profile of changes in response to acute stress. Additional studies are needed to determine how these basal and stress-related responses impact cognitive performance and whether these differences persist during cognitive testing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Low frequency transcranial magnetic stimulation of right posterior parietal cortex reduces reaction time to perithreshold low spatial frequency visual stimuli.

Research in humans and animal models suggests that visual responses in early visual cortical areas may be modulated by top-down influences from distant cortical areas, particularly in the frontal and parietal regions. The right posterior parietal cortex is part of a broad cortical network involved in aspects of visual search and attention, but its role in modulating activity in early visual cortical areas is less well understood. This study evaluated the influence of right posterior parietal cortex (PPC) on a direct measure of visual processing in humans. Contrast sensitivity (CS) and detection response times were recorded using a visual detection paradigm to two types of centrally-presented stimuli. Participants were tested on the detection task before, after, and 1 hour after low-frequency repetitive transcranial magnetic stimulation (rTMS) to the right PPC or to the scalp vertex. Low-frequency rTMS to the right PPC did not significantly change measures of contrast sensitivity, but increased the speed at which participants responded to visual stimuli of low spatial frequency. Response times returned to baseline 1-hour after rTMS. These data indicate that low frequency rTMS to the right PPC speeds up aspects of early visual processing, likely due to a disinhibition of the homotopic left posterior parietal cortex.

Cumulative sessions of repetitive transcranial magnetic stimulation (rTMS) build up facilitation to subsequent TMS-mediated behavioural disruptions.

A single session of repetitive transcranial magnetic stimulation (rTMS) can induce behavioural effects that outlast the duration of the stimulation train itself (off-line effects). Series of rTMS sessions on consecutive days are being used for therapeutic applications in a variety of disorders and are assumed to lead to the build-up of cumulative effects. However, no studies have carefully assessed this notion. In the present study we applied 30 daily sessions of 1 Hz rTMS (continuous train of 20 min) to repeatedly modulate activity in the posterior parietal cortex and associated neural systems in two intact cats. We assessed the effect on visuospatial orientation before and after each stimulation session. Cumulative sessions of rTMS progressively induced visuospatial neglect-like 'after-effects' of greater magnitude (from 5-10% to 40-50% error levels) and increasing spatial extent (from 90-75 degrees to 45-30 degrees eccentricity locations), affecting the visual hemifield contralateral to the stimulated hemisphere. Nonetheless, 60 min after each TMS session, visual detection-localization abilities repeatedly returned to baseline levels. Furthermore, no lasting behavioural effect could be demonstrated at any time across the study, when subjects were tested 1 or 24 h post-rTMS. We conclude that the past history of periodically cumulative rTMS sessions builds up a lasting 'memory', resulting in increased facilitation to subsequent TMS-induced disruptions. Such a phenomenon allows a behavioural effect of progressively higher magnitude, but equal duration, in response to individual TMS interventions.

From qualia to quantia: a system to document and quantify phosphene percepts elicited by non-invasive neurostimulation of the human occipital cortex.

The stimulation of the occipital cortex induces transient visual percepts, known as phosphenes. The characterization and analysis of the features of these visual qualia can provide a window into the physiology and neuroanatomy of cerebral visual networks of humans. Phosphenes can be reliably elicited in humans by a variety of invasive and non-invasive techniques that depolarize visual cortex neurons. Nonetheless both research into their neural basis and categorization of their features are ultimately reliant on subjective self-reports. A variety of methods have been employed to provide a more objective means of recording the localization and morphology of neurostimulation-induced phosphenes. In spite of these attempts, phosphenes remain difficult to measure. A standard technique able to both document the myriad of features characterizing phosphenes in a flexible manner and allow a systematic quantitative comparison across groups or repeated measures is lacking. We hereby provide detailed instructions on how to use off-the-shelf components to construct and implement the LTaP (laser tracking and painting system) system for a relatively objective and real-time documentation of the presence, shape, area, spatial location and distribution of phosphenes in visual space. We further provide experimental data demonstrating the feasibility and reliability of the LTaP system to accurately capture established features of phosphenes induced by transcranial magnetic stimulation (TMS) of occipital cortex.

Coping with spatial attention in real space: a low-cost portable testing system for the investigation of visuo-spatial processing in the human brain.

While two-dimensional stimuli may be easily presented with any computer, an apparatus which allows a range of stimuli to be presented in three dimensions is not easily or cheaply available to researchers or clinicians. To fill this gap, we have developed the Realspace Testing System (RTS) which addresses the need for a flexible and multimodal stimulus presentation system capable of displaying stimuli in a three-dimensional space with a high degree of temporal accuracy. The RTS is able to control 26 channels of visual or audio stimuli, to send trigger pulses during each trial to external devices, such as a transcranial magnetic stimulator, and to record subject responses during the testing sessions. The RTS is flexible, portable and can be used in laboratory or clinical settings as required while being built at a low cost using off the shelf components. We have tested the RTS by performing an exploratory experiment on the role of right posterior parietal cortex in visuo-spatial processing in conjunction with online transcranial magnetic stimulation (TMS) and verified that the system can accurately present stimuli as needed while triggering a TMS pulse during each trial at the required time. The RTS could be appealing and useful to a range of researchers or clinicians who may choose to use it much as we have designed it, or use it in its current state as a starting point to customize their stimulus control systems in real space.

Cancellation of visuoparietal lesion-induced spatial neglect.

In humans lesions of right visuoparietal cortex induce a neglect of the contralesional visual field that is characterized in its mild form by inattentiveness to objects and events and, in its more severe form, by a condition that has many features that are indistinguishable from blindness. Here we show that spatial neglect can be induced in cats by lesions of posterior and inferior visuoparietal cortex, and that the lesion-induced neglect can be cancelled by cooling deactivation of the same region in the opposite hemisphere.