Cortical spreading depression and the pathogenesis of brain disorders: a computational and neural network-based investigation

This paper reviews our recent studies of the role of cortical spreading depression (CSD) in the pathogenesis of brain disorders. Our investigation is a computational one, involving the development and utilization of a complex neuro-metabolic model of the interactions assumed to occur in the cortex during the passage of multiple CSD waves. Incorporating these neuro-metabolic changes of CSD within a neural network model of normoxic cortex produces cortical activation patterns during the passage of a CSD wave that, projected onto the visual fields, resemble the visual hallucinations observed during the migraine aura. When focal ischemia is simulated with the model, the evoked CSD waves are found to affect the expansion of the infarction into the ischemic penumbra. Our findings support the hypothesis that CSD does play an important pathogenic role in these and other neurological disorders, and suggest additional experimental studies that may further substantiate it.     

fMRI study relevant to the Mozart effect: Brain areas involved in spatial–temporal reasoning

Abstract

Behavioral studies, motivated by columnar cortical model predictions, have given evidence for music causally enhancing spatial–temporal reasoning. A wide range of behavioral experiments showed that listening to a Mozart Sonata (K.448) gave subsequent enhancements. An EEG coherence study gave evidence for a carryover from that Mozart Sonata listening condition to the subsequent spatial–temporal task in specific cortical regions. Here we present fMRI studies comparing cortical blood flow activation by the Mozart Sonata vs. other music. In addition to expected temporal cortex activation, we report dramatic statistically significant differences in activation by the Mozart Sonata (in comparison to Beethoven's Fur Elise and 1930s piano music) in dorsolateral pre-frontal cortex, occipital cortex and cerebellum, all expected to be important for spatial–temporal reasoning. It would be of great interest to explicitly test this expectation. We propose an fMRI study comparing (subject by subject) brain areas activated in music listening conditions and in spatial–temporal tasks. [Neurol Res 2001; 23: 683-690]     

Distinct spatiotemporal patterns of spreading depolarizations during early infarct evolution: evidence from real-time imaging

Experimental and clinical studies indicate that waves of cortical spreading depolarization (CSD) appearing in the ischemic penumbra contribute to secondary lesion growth. We used an embolic stroke model that enabled us to investigate inverse coupling of blood flow by laser speckle imaging (CBF_LSF) to CSD as a contributing factor to lesion growth already in the early phase after arterial occlusion. Embolization by macrospheres injected into the left carotid artery of anesthetized rats reduced CBF_LSF in the territories of the middle cerebral artery (MCA) (8/14 animals), the posterior cerebral artery (PCA) (2/14) or in less clearly defined regions (4/14). Analysis of MCA occlusions (MCAOs) revealed a first CSD wave starting off during ischemic decline at the emerging core region, propagating concentrically over large portions of left cortex. Subsequent recurrent waves of CSD did not propagate concentrically but preferentially circled around the ischemic core. In the vicinity of the core region, CSDs were coupled to waves of predominantly vasoconstrictive CBF_LSF responses, resulting in further decline of CBF in the entire inner penumbra and in expansion of the ischemic core. We conclude that CSDs and corresponding CBF responses follow a defined spatiotemporal order, and contribute to early evolution of ischemic territories.     

Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated l-glutamate-evoked firing, but not in the presence of GABA_A/B antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABA_A/B antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00879-6) contains supplementary material, which is available to authorized users.Key Words: Migraine, transcranial magnetic stimulation, GABA, glutamate, cortex     

Transcranial alternating current stimulation (tACS) modulates cortical excitability as assessed by TMS-induced phosphene thresholds

ObjectiveRecent developments in transcranial alternating current stimulation (tACS) provide a powerful approach to establish the functional roles of neuronal oscillatory activities in the human brain. Here, we investigated whether tACS can reach and modulate the excitability of the visual cortex in a frequency-dependent manner.MethodsWe measured the cortical excitability of the visual cortex using single pulse transcranial magnetic stimulation (TMS) while delivering tACS to the occipital region at different frequencies (5, 10, 20 and 40 Hz).ResultsWe found that tACS at 20 Hz decreased TMS–phosphene threshold (i.e., increased the excitability of the visual cortex) during the stimulation, whereas other frequencies did not affect TMS–phosphene thresholds.ConclusionsOur findings demonstrate direct interactions of tACS with the visual cortex in a frequency-dependent manner.SignificanceOur present work provides further demonstration of the potential of tACS as a method to selectively modulate the excitability of the visual cortex.     

Motor cortex excitability in transient global amnesia

Abstract.Objective: To investigate the physiology of motor cortical areas in patients with transient global amnesia (TGA).Materials and methods: We performed transcranial magnetic stimulation (TMS) and single photon emission computed tomography (SPECT) in 13 patients during and after the acute phase of a typical episode of TGA. Measures of cortical excitability included motor threshold (MT) to magnetic stimulation, cortical silent period (SP) duration and intracortical inhibition (ICI) using a paired-pulse TMS technique.Results: We found thalamic hypoperfusion and an ipsilateral significantly decreased ICI during the acute phase of TGA.Conclusions: Reduced activity in inhibitory circuits may explain why PET studies of patients with TGA showed neocortical hypometabolism. Our findings are consistent with the hypothesis that frontal cortex dysfunction probably due to damage affecting the thalamocortical circuits may play an important role in the pathogenesis of the syndrome.     

Effect of systemic kynurenine on cortical spreading depression and its modulation by sex hormones in rat

BackgroundThe aura symptoms in migraine are most likely due to cortical spreading depression (CSD). CSD is favored by NMDA receptor activation and increased cortical excitability. The latter probably explains why migraine with aura may appear when estrogen levels are high, like during pregnancy. Kynurenic acid, a derivative of tryptophan metabolism, is an endogenous NMDA receptor antagonist whose cerebral concentrations can be augmented by systemic administration of its precursor l-kynurenine.ObjectiveTo determine if exogenous administration of l-kynurenine is able to influence KCl-induced CSD in rat, if the effect is sex-dependent and if it differs in females between the phases of the estrous cycle.MethodsAdult Sprague–Dawley rats (n = 8/group) received intraperitoneal (i.p.) injections of l-kynurenine (L-KYN, 300 mg/kg), L-KYN combined with probenecid (L-KYN + PROB) that increases cortical concentration of KYNA by blocking its excretion from the central nervous system, probenecid alone (PROB, 200 mg/kg) or NaCl. Cortical kynurenic acid concentrations were determined by HPLC (n = 7). Thirty minutes after the injections, CSDs were elicited by application of 1 M KCl over the occipital cortex and recorded by DC electrocorticogram. In NaCl and L-KYN groups, supplementary females were added and CSD frequency was analyzed respective to the phases of the estrous cycle determined by vaginal smears.ResultsIn both sexes, PROB, L-KYN and L-KYN + PROB increased cortical kynurenic acid level. PROB, L-KYN and L-KYN + PROB with increasing potency decreased CSD frequency in female rats, while in males such an effect was significant only for L-KYN + PROB. The inhibitory effect of L-KYN on CSD frequency in females was most potent in diestrus.Conclusionl-Kynurenine administration suppresses CSD, most likely by increasing kynurenic acid levels in the cortex. Females are more sensitive to this suppressive effect of l-kynurenine than males. These results emphasize the role of sex hormones in migraine and open interesting novel perspectives for its preventive treatment.     

Sharply contoured theta waves are the human correlate of ponto-geniculo-occipital waves in the primary visual cortex

Objective

Ponto-geniculo-occipital (PGO) waves occurring along the visual axis are one of the hallmarks of REM sleep in experimental animals. In humans, direct evidence is scarce. There is no systematic study of PGO waves in the primary visual cortex.

Microglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex

Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer''s disease.     

Differential Spatiotemporal Alterations in Adrenoceptor mRNAs and Binding Sites in Cerebral Cortex Following Spreading Depression: Selective and Prolonged Up-Regulation of α1B-Adrenoceptors

Noradrenaline, an important transmitter in the CNS, is involved in cerebral plasticity and functional recovery after injury. Experimental brain injury, including KCl application onto the brain surface, induces a slow-moving cortical depolarization/depression wave called cortical spreading depression (CSD). Interestingly, CSD does not produce neuronal damage but can protect cortical neurons against subsequent neurotoxic insults, although the mechanisms involved are unknown. This study examined the status of α- and β-adrenoceptors (ARs) in cerebral cortex following CSD. Anesthetized rats had unilateral CSD induced by a 10-min topical application of KCl to the frontoparietal cortex and were killed at various times thereafter. Levels of α₁-, α₂-, β₁-, and β₂-AR mRNA and binding were examined usingin situhybridization histochemistry and radioligand autoradiography. Levels of α_1b-AR mRNA in the affected neocortex were significantly increased by 20–40% at 1, 2, and 7 days (P ≤ 0.01) compared with contralateral levels, but were not significantly above control values at 2 and 4 weeks after CSD induction. Cortical α_1B-AR binding sites were also increased by 45–65% 1 and 2 weeks (P ≤ 0.01) after CSD in a similar, but delayed, profile to α_1b-AR mRNA. CSD rapidly increased β₁-AR mRNA by 45% at 1 h (P ≤ 0.01) and produced a delayed decrease of 25% in α_2a-AR mRNA at 2 days and 1 week (P ≤ 0.05), but had no effect on corresponding levels of binding sites. In contrast, CSD had no effect on the remaining AR-subtype mRNAs or binding levels in neocortex under identical conditions. These results reveal a long-term up-regulation of α_1B-ARs induced by an acute cortical stimulation/depression. Subtype-selective responses of ARs to CSD reflect an important differential regulation of expression of each receptorin vivoand suggest that α_1B-ARs are particularly likely to be involved in cortical adaptive responses to physical injury at both local and distant locations.     

Activity of hypothalamic thermosensitive neurons during cortical spreading depression in the rat

Effects of single waves of cortical spreading depression (CSD) on unit activity of the ipsilateral preoptic and anterior hypothalamic (PO/AH) neurones were studied in urethane-anesthetized rats.When CSD entered the frontal cortex, the firing rate of teh majority, (85%, 22/26 units) of Po/AH warm-sensitive neurons decreased for 1.4–14.2 min and the remaining 4 neurons were unaffected. In contrast, 10 (77%) of the 13 cold-sensitive neurons increased their firing rates for 1.2–10.4 min after the CSD entrance of the frontal cortex. Of the remaining 3 neurons, two decreased their firing rates and one showed no change during CSD. Thirteen (76%) of the 17 thermally insensitive neurons were not affected by CSD, but the remaining 4 neurons decreased their firing rates slightly for about 1.4 min.The most critical cortical region responsible for the activity change of the PO/AH thermosensitive neurons during CSD was found to lie in the sulcal prefrontal cortex by observing the effect of a single CSD elicited separately from the occipital and the frontal cortex on the same PO/AH neurons (a double-CSD technique).The result, together with the previous ones on thermoregulatory responses during the frontal CSD, suggests that the sulcal prefrontal cortex exerts a tonic influence on the activity of the hypothalamic thermosensitive neurons and is involved in the central control of thermoregulation.     

Clinical relevance of cortical spreading depression in neurological disorders: migraine,malignant stroke,subarachnoid and intracranial hemorrhage,and traumatic brain injury

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.     

Spontaneous modulations of high-frequency cortical activity

ObjectiveWe clarified the clinical and mechanistic significance of physiological modulations of high-frequency broadband cortical activity associated with spontaneous saccadic eye movements during a resting state.MethodsWe studied 30 patients who underwent epilepsy surgery following extraoperative electrocorticography and electrooculography recordings. We determined whether high-gamma activity at 70–110 Hz preceding saccade onset would predict upcoming ocular behaviors. We assessed how accurately the model incorporating saccade-related high-gamma modulations would localize the primary visual cortex defined by electrical stimulation.ResultsThe dynamic atlas demonstrated transient high-gamma suppression in the striatal cortex before saccade onset and high-gamma augmentation subsequently involving the widespread posterior brain regions. More intense striatal high-gamma suppression predicted the upcoming saccade directed to the ipsilateral side and lasting longer in duration. The bagged-tree-ensemble model demonstrated that intense saccade-related high-gamma modulations localized the visual cortex with an accuracy of 95%.ConclusionsWe successfully animated the neural dynamics supporting saccadic suppression, a principal mechanism minimizing the perception of blurred vision during rapid eye movements. The primary visual cortex per se may prepare actively in advance for massive image motion expected during upcoming prolonged saccades.SignificanceMeasuring saccade-related electrocorticographic signals may help localize the visual cortex and avoid misperceiving physiological high-frequency activity as epileptogenic.     

Microstimulation-evoked neural responses in visual cortex are depth dependent

BackgroundCortical visual prostheses often use penetrating electrode arrays to deliver microstimulation to the visual cortex. To optimize electrode placement within the cortex, the neural responses to microstimulation at different cortical depths must first be understood.ObjectiveWe investigated how the neural responses evoked by microstimulation in cortex varied with cortical depth, of both stimulation and response.MethodsA 32-channel single shank electrode array was inserted into the primary visual cortex of anaesthetized rats, such that it spanned all cortical layers. Microstimulation with currents up to 14 μA (single biphasic pulse, 200 μs per phase) was applied at depths spanning 1600 μm, while simultaneously recording neural activity on all channels within a response window 2.25–11 ms.ResultsStimulation elicited elevated neuronal firing rates at all depths of cortex. Compared to deep sites, superficial stimulation sites responded with higher firing rates at a given current and had lower thresholds. The laminar spread of evoked activity across cortical depth depended on stimulation depth, in line with anatomical models.ConclusionStimulation in the superficial layers of visual cortex evokes local neural activity with the lowest thresholds, and stimulation in the deep layers evoked the most activity across the cortical column. In conjunction with perceptual reports, these data suggest that the optimal electrode placement for cortical microstimulation prostheses has electrodes positioned in layers 2/3, and at the top of layer 5.     

Spreading depression in human neocortical slices

Cortical spreading depression (CSD) occurrence has been suggested to be associated with seizures, migraine aura, head injury and brain ischemia-infarction. Only few studies identified CSD in human neocortical slices and no comprehensive study so far evaluated this phenomenon in human. Using the neocortical tissue excised for treatment of intractable epilepsy, we aimed to investigate CSD in human. CSD was induced by KCl injection and by modulating T-type Ca²⁺ currents in incubated human neocortical tissues in an interphase mode. The DC-fluctuations were recorded by inserting microelectrodes into different cortical layers. Local injection of KCl triggered single CSD that propagated at 3.1±0.1 mm/min. Repetitive CSD also occurred spontaneously during long lasting application (5 h) of the T-type Ca²⁺ channel blockers amiloride (50 μM) or NiCl₂ (10 μM) which was concomitant with a reversible extracellular potassium increase up to 50 mM. CSD could be blocked by the N-methyl- -aspartate receptor antagonist 2-amino-5-phosphonovaleric acid in all cases. The results demonstrate that modulation of the Ca²⁺ dynamics conditioned human neocortical slices and increased their susceptibility to generate CSD. Furthermore, these data indicate that glutamatergic pathway plays a role in CSD phenomenon in human.     

Cortical representation of conditioned eye blink in the rabbit studied by a functional ablation technique

Conditioned eye blink was established in rabbits by reinforcing visual or auditory conditioned stimulus (CS) (400 msec) with corneal air puffs (UCS). After 90% correct responses had been attained, single waves of cortical spreading depression (CSD) were elicited by microinjection of 25% KCl into the frontal or occipital cortex and the slow potential change (SPC) was recorded with implanted AgAgCl electrodes. Frontal injection into the hemicortex contralateral to the blinking eye suppressed the conditioned eye blink as soon as the negative SPC invaded the motor cortex. Recovery started 4 min later and was completed after 18 or 23 min when using auditory or visual CS respectively. Occipital injection of KCl caused a deep but incomplete suppression of the visually conditioned eye blink and a much weaker impairment of the auditory CS. Complete blockade of the conditioned eye blink developed when CSD reached the frontal cortex. CSD in the ipsilateral hemisphere had similar but less pronounced effects. It is concluded that the cortical projection of the CS is important but not indispensable for the performance of the conditioned eye blink.     

Functional Differentiation of Mouse Visual Cortical Areas Depends upon Early Binocular Experience

The mammalian visual cortex contains multiple retinotopically defined areas that process distinct features of the visual scene. Little is known about what guides the functional differentiation of visual cortical areas during development. Recent studies in mice have revealed that visual input from the two eyes provides spatiotemporally distinct signals to primary visual cortex (V1), such that contralateral eye-dominated V1 neurons respond to higher spatial frequencies than ipsilateral eye-dominated neurons. To test whether binocular visual input drives the differentiation of visual cortical areas, we used two-photon calcium imaging to characterize the effects of juvenile monocular deprivation (MD) on the responses of neurons in V1 and two higher visual areas, LM (lateromedial) and PM (posteromedial). In adult mice of either sex, we find that MD prevents the emergence of distinct spatiotemporal tuning in V1, LM, and PM. We also find that, within each of these areas, MD reorganizes the distinct spatiotemporal tuning properties driven by the two eyes. Moreover, we find a relationship between speed tuning and ocular dominance in all three areas that MD preferentially disrupts in V1, but not in LM or PM. Together, these results reveal that balanced binocular vision during development is essential for driving the functional differentiation of visual cortical areas. The higher visual areas of mouse visual cortex may provide a useful platform for investigating the experience-dependent mechanisms that set up the specialized processing within neocortical areas during postnatal development.SIGNIFICANCE STATEMENT Little is known about the factors guiding the emergence of functionally distinct areas in the brain. Using in vivo Ca²⁺ imaging, we recorded visually evoked activity from cells in V1 and higher visual areas LM (lateromedial) and PM (posteromedial) of mice. Neurons in these areas normally display distinct spatiotemporal tuning properties. We found that depriving one eye of normal input during development prevents the functional differentiation of visual areas. Deprivation did not disrupt the degree of speed tuning, a property thought to emerge in higher visual areas. Thus, some properties of visual cortical neurons are shaped by binocular experience, while others are resistant. Our study uncovers the fundamental role of binocular experience in the formation of distinct areas in visual cortex.     

Increased intrinsic brain connectivity between pons and somatosensory cortex during attacks of migraine with aura

The neurological disturbances of migraine aura are caused by transient cortical dysfunction due to waves of spreading depolarization that disrupt neuronal signaling. The effects of these cortical events on intrinsic brain connectivity during attacks of migraine aura have not previously been investigated. Studies of spontaneous migraine attacks are notoriously challenging due to their unpredictable nature and patient discomfort. We investigated 16 migraine patients with visual aura during attacks and in the attack‐free state using resting state fMRI. We applied a hypothesis‐driven seed‐based approach focusing on cortical visual areas and areas involved in migraine pain, and a data‐driven independent component analysis approach to detect changes in intrinsic brain signaling during attacks. In addition, we performed the analyses after mirroring the MRI data according to the side of perceived aura symptoms. We found a marked increase in connectivity during attacks between the left pons and the left primary somatosensory cortex including the head and face somatotopic areas (peak voxel: P = 0.0096, (x, y, z ) = (?54, ?32, 32), corresponding well with the majority of patients reporting right‐sided pain. For aura‐side normalized data, we found increased connectivity during attacks between visual area V5 and the lower middle frontal gyrus in the symptomatic hemisphere (peak voxel: P = 0.0194, (x, y, z ) = (40, 40, 12). The present study provides evidence of altered intrinsic brain connectivity during attacks of migraine with aura, which may reflect consequences of cortical spreading depression, suggesting a link between aura and headache mechanisms. Hum Brain Mapp 38:2635–2642, 2017 . © 2017 Wiley Periodicals, Inc.     

Changes in cortical protein markers of iron transport with gender,major depressive disorder and suicide

Abstract

Objectives: The objective of this study was to determine whether a breakdown in proteins regulating cortical iron homeostasis could be involved in the pathophysiology of mood disorders.

Methods: Levels of select proteins responsible for cortical iron transport were quantitated by Western blotting of Brodmann’s (BA) areas 6 and 10 from patients with major depressive disorder (n?=?13), bipolar disorder (n?=?12) and age/sex matched controls (n?=?13).

Results: We found the inactive form of ceruloplasmin was lower in BA 6 from males compared to females. Levels of copper containing ceruloplasmin was lower in BA 6 from suicide completers whilst levels of amyloid precursor protein, TAU and transferrin were higher in BA 10 from those individuals. The level of prion protein was lower in BA 6 from subjects with major depressive disorder.

Conclusions: Our data suggests that perturbation in cortical iron transport proteins is not prevalent in mood disorders. By contrast, our data suggests changes in iron transport proteins in BA 6 and BA 10 are present after suicide completion. If these changes were present before death, they could have had a role in the genesis of the contemplation and completion of suicide.