A Cross-Sectional Time Course of COVID-19 Related Worry, Perceived Stress, and General Anxiety in the Context of Post-Traumatic Stress Disorder-like Symptomatology.

The COVID-19 pandemic within the United States of America resulted in over 800,000 deaths as of February 2022 and has been addressed by social distancing or stay-at-home measures. Collective prolonged multimodal trauma on this scale is likely to elicit symptomatology in the general population consistent with post-traumatic stress disorder (PTSD), somatization, anxiety, and stress. The psychological component of this response contributes substantially to the burden of this disease worldwide. This cross-sectional study examines the relationship between COVID-19-related concern, anxiety, and perceived stress on PTSD-like symptomatology over the course of the COVID-19 pandemic. Participants were recruited via social media within the United States of America between 8th May 2020 and 11th August 2021 to complete an internet questionnaire including mood, personality, and COVID-19-specific scales. General anxiety and PTSD-like symptomatology were above the screening cutoffs for most respondents. These measures increased in severity over the pandemic, with the change point of our Concern scale preceding that of the other significant measures. Measures of COVID-19-related concern, generalized anxiety, and PTSD-like symptomatology were strongly correlated with each other. Anxiety, perceived stress, and PTSD-like symptomatology are strongly interrelated, increase with pandemic length, and are linked to reported levels of concern over COVID-19. These observations may aid future research and policy as the pandemic continues.

During vigilance to painful stimuli: slower response rate is related to high trait anxiety, whereas faster response rate is related to high state anxiety.

A pathological increase in vigilance, or hypervigilance, may be related to pain intensity in some clinical pain syndromes and may result from attention bias to salient stimuli mediated by anxiety. During a continuous performance task where subjects discriminated painful target stimuli from painful nontargets, we measured detected targets (hits), nondetected targets (misses), nondetected nontargets (correct rejections), and detected nontargets (false alarms). Using signal detection theory, we calculated response bias, the tendency to endorse a stimulus as a target, and discriminability, the ability to discriminate a target from nontarget. Owing to the relatively slow rate of stimulus presentation, our primary hypothesis was that sustained performance would result in a more conservative response bias reflecting a lower response rate over time on task. We found a more conservative response bias with time on task and no change in discriminability. We predicted that greater state and trait anxiety would lead to a more liberal response bias. A multivariable model provided partial support for our prediction; high trait anxiety related to a more conservative response bias (lower response rate), whereas high state anxiety related to a more liberal bias. This inverse relationship of state and trait anxiety is consistent with reports of effects of state and trait anxiety on reaction times to threatening stimuli. In sum, we report that sustained attention to painful stimuli was associated with a decrease in the tendency of the subject to respond to any stimulus over time on task, whereas the ability to discriminate target from nontarget remains unchanged.NEW & NOTEWORTHY During a series of painful stimuli requiring subjects to respond to targets, we separated response willingness from ability to discriminate targets from nontargets. Response willingness declined during the task, with no change in subjects' ability to discriminate, consistent with previous vigilance studies. High trait anxious subjects were less willing to respond and showed slower reaction times to hits than low anxious subjects. This study reveals an important role of trait anxiety in pain vigilance.

Mapping tracts in the human subthalamic area by 11.7T ex vivo diffusion tensor imaging.

The cortico-basal ganglia-thalamo-cortical feedback loops that consist of distinct white matter pathways are important for understanding in vivo imaging studies of functional and anatomical connectivity, and for localizing subthalamic white matter structures in surgical approaches for movement disorders, such as Parkinson's disease. Connectomic analysis in animals has identified fiber connections between the basal ganglia and thalamus, which pass through the fields of Forel, where other fiber pathways related to motor, sensory, and cognitive functions co-exist. We now report these pathways in the human brain on ex vivo mesoscopic (250 µm) diffusion tensor imaging and on tractography. The locations of the tracts were identified relative to the adjacent gray matter structures, such as the internal and external segments of the globus pallidus; the zona incerta; the subthalamic nucleus; the substantia nigra pars reticulata and compacta; and the thalamus. The connectome atlas of the human subthalamic region may serve as a resource for imaging studies and for neurosurgical planning.

Multi-Regional Adaptation in Human Auditory Association Cortex.

In auditory cortex, neural responses decrease with stimulus repetition, known as adaptation. Adaptation is thought to facilitate detection of novel sounds and improve perception in noisy environments. Although it is well established that adaptation occurs in primary auditory cortex, it is not known whether adaptation also occurs in higher auditory areas involved in processing complex sounds, such as speech. Resolving this issue is important for understanding the neural bases of adaptation and to avoid potential post-operative deficits after temporal lobe surgery for treatment of focal epilepsy. Intracranial electrocorticographic recordings were acquired simultaneously from electrodes implanted in primary and association auditory areas of the right (non-dominant) temporal lobe in a patient with complex partial seizures originating from the inferior parietal lobe. Simple and complex sounds were presented in a passive oddball paradigm. We measured changes in single-trial high-gamma power (70-150 Hz) and in regional and inter-regional network-level activity indexed by cross-frequency coupling. Repetitive tones elicited the greatest adaptation and corresponding increases in cross-frequency coupling in primary auditory cortex. Conversely, auditory association cortex showed stronger adaptation for complex sounds, including speech. This first report of multi-regional adaptation in human auditory cortex highlights the role of the non-dominant temporal lobe in suppressing neural responses to repetitive background sounds (noise). These results underscore the clinical utility of functional mapping to avoid potential post-operative deficits including increased listening difficulties in noisy, real-world environments.

Human Thalamic Somatosensory Nucleus (Ventral Caudal, Vc) as a Locus for Stimulation by INPUTS from Tactile, Noxious and Thermal Sensors on an Active Prosthesis.

The forebrain somatic sensory locus for input from sensors on the surface of an active prosthesis is an important component of the Brain Machine Interface. We now review the neuronal responses to controlled cutaneous stimuli and the sensations produced by Threshold Stimulation at Microampere current levels (TMIS) in such a locus, the human thalamic Ventral Caudal nucleus (Vc). The responses of these neurons to tactile stimuli mirror those for the corresponding class of tactile mechanoreceptor fiber in the peripheral nerve, and TMIS can evoke sensations like those produced by the stimuli that optimally activate each class. These neuronal responses show a somatotopic arrangement from lateral to medial in the sequence: leg, arm, face and intraoral structures. TMIS evoked sensations show a much more detailed organization into anterior posteriorly oriented rods, approximately 300 microns diameter, that represent smaller parts of the body, such as parts of individual digits. Neurons responding to painful and thermal stimuli are most dense around the posterior inferior border of Vc, and TMIS evoked pain sensations occur in one of two patterns: (i) pain evoked regardless of the frequency or number of spikes in a burst of TMIS; and (ii) the description and intensity of the sensation changes with increasing frequencies and numbers. In patients with major injuries leading to loss of somatic sensory input, TMIS often evokes sensations in the representation of parts of the body with loss of sensory input, e.g., the phantom after amputation. Some patients with these injuries have ongoing pain and pain evoked by TMIS of the representation in those parts of the body. Therefore, thalamic TMIS may produce useful patterned somatotopic feedback to the CNS from sensors on an active prosthesis that is sometimes complicated by TMIS evoked pain in the representation of those parts of the body.

Stroke of bad luck?

We hypothesized that distinct acute right hemisphere lesions disrupt separate components of valuation and emotional response to winning and losing money and of emotional empathy in observing a partner win or lose money. We measured skin conductance response (SCR) and ratings of emotions when acute right hemisphere stroke patients or healthy controls won or lost money in roulette, or when they watched a partner win or lose. Our results showed that percentage of damage after stroke to right anterior insula and frontal operculum negatively correlated with both SCR to winning and losing and difference between rating wins versus losses.

Neuronal responses to tactile stimuli and tactile sensations evoked by microstimulation in the human thalamic principal somatic sensory nucleus (ventral caudal).

The normal organization and plasticity of the cutaneous core of the thalamic principal somatosensory nucleus (ventral caudal, Vc) have been studied by single-neuron recordings and microstimulation in patients undergoing awake stereotactic operations for essential tremor (ET) without apparent somatic sensory abnormality and in patients with dystonia or chronic pain secondary to major nervous system injury. In patients with ET, most Vc neurons responded to one of the four stimuli, each of which optimally activates one mechanoreceptor type. Sensations evoked by microstimulation were similar to those evoked by the optimal stimulus only among rapidly adapting neurons. In patients with ET, Vc was highly segmented somatotopically, and vibration, movement, pressure, and sharp sensations were usually evoked by microstimulation at separate sites in Vc. In patients with conditions including spinal cord transection, amputation, or dystonia, RFs were mismatched with projected fields more commonly than in patients with ET. The representation of the border of the anesthetic area (e.g., stump) or of the dystonic limb was much larger than that of the same part of the body in patients with ET. This review describes the organization and reorganization of human Vc neuronal activity in nervous system injury and dystonia and then proposes basic mechanisms.

Effect of N-arachidonoyl-l-serine on human cerebromicrovascular endothelium.

N-arachidonoyl-l-serine (ARA-S) is an endogenous lipid, chemically related to the endocannabinoid, N-arachidonoyl ethanolamine (i.e., anandamide) and with similar physiologic and pathophysiologic functions. Reports indicate that ARA-S possesses vasoactive and neuroprotective properties resembling those of cannabinoids. However, in contrast to cannabinoids, ARA-S binds weakly to its known classical receptors, CB1 and CB2, and is therefore considered to be a 'cannabinoid-like' substance. The originally described ARA-S induced-endothelial-dependent vasorelaxation was not abrogated by CB1, CB2 receptor antagonists or TRPV1 competitive inhibitor. The present report demonstrates that ARA-S enhances the fluorescence staining of both cannabinoid receptors (CB1 and CB2) in human brain endothelial cells (HBEC). This reaction is specific since it was reduced by respective selective receptor antagonist (SR141716A and SR141728A). ARA-S alone or in the presence of ET-1 was shown to alter the cytoskeleton (actin). Both ARA-S stimulated phosphorylation of various kinases (MAPK, Akt, JNK and c-JUN) and alteration of cytoskeleton are mediated via CB1, CB2 and TRPV1 receptors. The findings also showed the involvement of Rho/Rock and PI3/Akt/NO pathways in the ARA-S-induced phosphorylation of kinases and actin reorganization in HBEC. All of the above mentioned ARA-S-induced effects were reduced by the treatment with LY294002 (inhibitor of PI3/Akt kinase), except MAPK kinase. In addition, MAPK, JNK, c-JUN phosphorylation were inhibited by H1152 (inhibitor of Rho/ROCK kinase), except Akt kinase. Furthermore, PI3/Akt pathway was inhibited by pretreatment with l-NAME (inhibitor of NOS). The findings suggest that ARA-S is a modulator of Rho kinase and may play a critical role in the regulation of its activity and subsequent effects on the cytoskeleton and its role in supporting essential cell functions like vasodilation, proliferation and movement.

Postoperative symptoms of psychosis after deep brain stimulation in patients with Parkinson's disease.

OBJECT: Cases of postoperative psychosis in Parkinson's disease patients receiving deep brain stimulation (DBS) treatment have previously been published. However, the magnitude of symptom incidence and the clinical risk factors are currently unknown. This retrospective study sheds light on these issues by investigating psychosis in a group of 128 Parkinson's disease patients who received DBS implants. METHODS: A retrospective chart review was performed to obtain surgery dates, follow-up clinic visit dates, and associated stimulation parameter settings (contacts in use and the polarity of each along with stimulation voltage, frequency, and pulse width) for each patient. Unified Parkinson's Disease Rating Scale II Thought Disorder scores, used as a clinical assessment tool to evaluate the presence of psychosis at each visit, were also collected. The data were compiled into a database and analyzed. RESULTS: The lifetime incidence of psychosis in this cohort of patients was 28.1%. The data suggest that risk of psychosis remains fairly constant throughout the first 5 years after implantation of a DBS system and that patients older at the time of receiving the first DBS implant are not only more likely to develop psychosis, but also to develop symptoms sooner than their younger counterparts. Further analysis provides evidence that psychosis is largely independent of the clinically used electrode contact and of stimulation parameters prior to psychosis onset. CONCLUSIONS: Although symptoms of psychosis are widely seen in patients with Parkinson's disease in the years following stimulator placement, results of the present suggest that most psychoses occurring postoperatively are likely independent of implantation and stimulation settings.

Adaptation of high-gamma responses in human auditory association cortex.

This study investigates adaptation of high-frequency cortical responses [>60 Hz; high-gamma (HG)] to simple and complex sounds in human nonprimary auditory cortex. We used intracranial electrocorticographic recordings to measure event-related changes in HG power as a function of stimulus probability. Tone and speech stimuli were presented in a series of traditional oddball and control paradigms. We hypothesized that HG power attenuates with stimulus repetition over multiple concurrent time scales in auditory association cortex. Time-frequency analyses were performed to identify auditory-responsive sites. Single-trial analyses and quantitative modeling were then used to measure trial-to-trial changes in HG power for high (frequent), low (infrequent), and equal (control) stimulus probabilities. Results show strong reduction of HG responses to frequently repeated tones and speech, with no differences in responses to infrequent and equal-probability stimuli. Adaptation of the HG frequent response, and not stimulus-acoustic differences or deviance-detection enhancement effects, accounted for the differential responses observed for frequent and infrequent sounds. Adaptation of HG responses showed a rapid onset (less than two trials) with slower adaptation between consecutive, repeated trials (2-10 s) and across trials in a stimulus block (∼7 min). The auditory-evoked N100 response also showed repetition-related adaptation, consistent with previous human scalp and animal single-unit recordings. These findings indicate that HG responses are highly sensitive to the regularities of simple and complex auditory events and show adaptation on multiple concurrent time scales in human auditory association cortex.

Reliability of early cortical auditory gamma-band responses.

OBJECTIVE: To evaluate the test-retest reliability of event-related power changes in the 30-150 Hz gamma frequency range occurring in the first 150 ms after presentation of an auditory stimulus. METHODS: Repeat intracranial electrocorticographic (ECoG) recordings were performed with 12 epilepsy patients, at ≥1-day intervals, using a passive odd-ball paradigm with steady-state tones. Time-frequency matching pursuit analysis was used to quantify changes in gamma-band power relative to pre-stimulus baseline. Test-retest reliability was estimated based on within-subject comparisons (paired t-test, McNemar's test) and correlations (Spearman rank correlations, intra-class correlations) across sessions, adjusting for within-session variability. Reliability estimates of gamma-band response robustness, spatial concordance, and reproducibility were compared with corresponding measurements from concurrent auditory evoked N1 responses. RESULTS: All patients showed increases in gamma-band power, 50-120 ms post-stimulus onset, that were highly robust across recordings, comparable to the evoked N1 responses. Gamma-band responses occurred regardless of patients' performance on behavioral tests of auditory processing, medication changes, seizure focus, or duration of test-retest interval. Test-retest reproducibility was greatest for the timing of peak power changes in the high-gamma range (65-150 Hz). Reliability of low-gamma responses and evoked N1 responses improved at higher signal-to-noise levels. CONCLUSIONS: Early cortical auditory gamma-band responses are robust, spatially concordant, and reproducible over time. SIGNIFICANCE: These test-retest ECoG results confirm the reliability of auditory gamma-band responses, supporting their utility as objective measures of cortical processing in clinical and research studies.

Reversal of postischemic hypoperfusion by tempol: endothelial signal transduction mechanism.

This report entails in vivo and in vitro studies concerned with free radical species involved in brain ischemia. The participation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the early manifestation of cerebral ischemia/reperfusion was investigated in gerbils exposed to transient global ischemia using 4-OH-2,2,6,6-tetramethylpiperidine-1-oxyl (TPL), a well-known antioxidant. TPL treatment reversed cerebral postischemic hypoperfusion and tissue edema in these animals. The findings are consistent with ROS/RNS participation in tissue injury and the reduction of cerebromicrovascular blood flow (CBF) during postischemic recirculation. The activation/deactivation of signal transduction pathway by oxidation/antioxidation [i.e., using hydrogen peroxide (H2O2)/TPL] was evaluated in cultured human brain endothelial cells (HBEC) to assess the involvement of endothelial-dependent mechanisms. The data showed that H2O2 activates various "stress" kinases and vasodilalator-stimulated phosphoprotein (VASP); activation of this pathway was reduced by inhibitors of Rho- or IP-3 kinases, as well as TPL. H2O2 also induced cytoskeleton (actin) rearrangements in HBEC; this effect was prevented by inhibitors of Rho/IP3 kinase or TPL. The observed activation/deactivation of H2O2-induced "stress" kinase is in agreement with the reported capacity of ROS/RNS to stimulate the oxidative signal transduction pathway. The noted TPL reduction of H2O2-induced phosphorylation of kinase strongly suggests that the beneficial effect of TPL implicates the stress signal transduction pathway. This may represent a mechanism for the cerebral postischemic manifestations observed by in vivo experiments.

Review of motor and phantom-related imagery.

This review presents a summary of recent efforts in understanding the systems of the brain involved in motor imagery. Motor imagery likely involves many cortical regions in its generation, but in action may also involve subcortical structures. The parietal lobe seems to be particularly important, as demonstrated by brain imaging studies and patients with lesions of this region. Brain activity correlated with imagery may be related to an efference copy used to compare with peripheral sensory signals for the correction of movement. Amputees with phantom representations have also provided valuable information in this field, as they demonstrate cortical reorganization, which also alters imagery of the missing limb. The following summary explores the recent difficult and challenging studies used to tease out motor imagery in man.

Attention to painful cutaneous laser stimuli evokes directed functional interactions between human sensory and modulatory pain-related cortical areas.

The human 'pain network' includes cortical areas that are activated during the response to painful stimuli (termed category 1) or during psychological processes that modulate pain, for example, distraction (termed category 2). These categories include parts of the parasylvian (PS), medial frontal (MF), and paracentral cortex (S1&M1). Here we test the hypothesis that causal interactions both within and between category 1 and category 2 modules occur during attention to a painful stimulus. Event-related causality (ERC) was calculated from local field potentials recorded directly from these cortical areas during the response to a painful cutaneous laser stimulus in patients being monitored for epilepsy. The number of electrodes involved in pairs with significant ERC in category 1 was greater for pre-stimulus vs post-stimulus and for attention vs distraction. This is consistent with our prior evidence that the category 1 'pain network' changes rapidly with time intervals and tasks. In contrast, the interaction between categories was often unchanged or stable across intervals and tasks, particularly in MF. The proportion of contacts involved in interactions with PS was greater during distraction vs attention while activation was less, which suggests that distraction involves an inhibitory process in PS. Functional interactions between categories were overwhelmingly in the direction from category 2>1, particularly for contacts in MF which often had a driver role. These results demonstrate that MF is densely interconnected throughout the 'pain network' so that stimulation of MF might be used to disrupt the 'pain network' as a therapy for pain.

Thalamic neuronal and EMG activity in psychogenic dystonia compared with organic dystonia.

BACKGROUND: This is a retrospective analysis of thalamic neuronal and electromyogram activities between subjects with organic dystonia and a subject with psychogenic dystonia in whom a thalamotomy was carried out before the diagnosis of psychogenic dystonia was made. RESULTS: The signal-to-noise ratio in the lowest frequency band (dystonia frequency < 0.76 Hz) in the electromyogram was not significantly different by diagnosis or muscle. The coherence at dystonia frequency for wrist flexors X biceps electromyograms was significantly higher in organic dystonia, whereas the phase was not apparently different from zero for either diagnosis. In a thalamic pallidal relay nucleus (ventral oral posterior), neuronal firing rates were not apparently different between psychogenic and organic dystonia. The neuronal signal-to-noise ratio in ventral oral posterior was significantly higher in organic dystonia than in psychogenic dystonia, whereas both were greater than in controls with chronic pain. Spike X electromyogram coherence apparently was not different between psychogenic and organic dystonia. The proportion of thalamic cells responding to joint movements was higher in the cerebellar relay nucleus (ventral intermediate) of psychogenic dystonia than in organic dystonia. CONCLUSIONS: These results suggest that some features, such as firing rates and thalamic reorganization, are similar in psychogenic and organic dystonia. Other features differ, such as the coherence between the electromyograms from different muscles and the thalamic neuronal signal-to-noise ratio, which may reflect pathophysiological factors in organic dystonia. © 2011 Movement Disorder Society.

Demonstration of motor imagery movement and phantom movement-related neuronal activity in human thalamus.

Functional imaging studies show that motor imagery activates multiple structures in the human forebrain. We now show that phantom movements in an amputee and imagined movements in intact individuals elicit responses from neurons in several human thalamic nuclei. These include the somatic sensory nucleus receiving input from the periphery (ventral caudal), and the motor nuclei receiving input from the cerebellum [ventral intermediate (Vim)] and the basal ganglia [ventral oral posterior (Vop)]. Seven neurons in the amputee showed phantom movement-related activity (three Vim, two Vop, and two ventral caudal). In addition, seven neurons in a group of three controls showed motor imagery-related activity (four Vim and three Vop). These studies were performed during single neuron recording sessions in patients undergoing therapeutic treatment of phantom pain, tremor, and chronic pain conditions by thalamic stimulation. The activity of neurons in these sensory and motor nuclei, respectively, may encode the expected sensory consequences and the dynamics of planned movements.

Selective denervation of the levator scapulae muscle: an amendment to the Bertrand procedure for the treatment of spasmodic torticollis.

OBJECT: The purpose of this cadaveric study was to explore a modification to the Bertrand procedure for the treatment of spasmodic torticollis, namely the denervation of the levator scapulae (LS) muscle for laterocollis. METHODS: The authors performed a series of 9 cadaveric dissections. Five were done to identify the anterior innervation of the LS, and the remaining 4 were to identify the tendinous insertions of the LS onto the lateral masses of the cervical spine via a posterior approach. The nerve supply to the LS from the anterior divisions of the C-3 and C-4 nerve roots and the contribution from the dorsal scapular nerve were identified over the anterior surface of the muscle. RESULTS: The C-3 and C-4 nerve root branches were situated within 2 cm of each other and inferior to the punctum nervosum. The dorsal scapular contribution was clearly identified in 2 cadavers. Selective denervation of this muscle is possible through the same posterior triangle incision used for denervating the sternocleidomastoid muscle of its accessory nerve branches. This approach will be helpful in patients with laterocollis contralateral to the direction of chin turning. The authors compare this approach to the posterior approach for sectioning the insertions of the LS muscle onto the C1-4 posterior tubercles. The latter approach is appropriate for ipsilateral laterocollis. CONCLUSIONS: The posterior triangle approach for denervating the LS muscle is a safe and easy addition to the Bertrand procedure and can be helpful in selected cases of torticollis with a laterocollis component.

Quantitative somatic sensory testing and functional imaging of the response to painful stimuli before and after cingulotomy for obsessive-compulsive disorder (OCD).

The middle cingulate cortex (MCC) has been implicated in pain processing by studies of cingulotomy for chronic pain and imaging studies documenting increased MCC blood flow in response to acute pain. The only previous report of quantitative sensory testing following cingulotomy described increased intensity and unpleasantness ratings of painful hot and cold stimuli in a single patient with psychiatric disease. We now report a case in which perception of pain and temperature was assessed before and after cingulotomy for obsessive-compulsive disorder (OCD). Positron emission tomographic (PET) studies of the blood flow response to acute pain were carried out using a single subject design which allowed for statistical evaluation of postoperative blood flow changes in this case. Postoperatively, the patient demonstrated increased intensity and unpleasantness ratings of painful thermal waterbath stimuli. The PET studies demonstrated preoperative contact heat pain-evoked activation of the bilateral MCC/SMA (supplementary motor area) and the left (contralateral) fronto-parietal operculum. Postoperative pain-evoked activation was demonstrated in the right (ipsilateral) parasylvian cortex but not of the MCC/SMA. Prior studies of forebrain lesions, and of cortical synchrony during the application of painful stimuli suggest the presence of functional connectivity between components of the MCC/SMA and the fronto-parietal opercula. Therefore present results suggest that cingulate lesions disinhibit ipsilateral parasylvian cortex and so are independent evidence of functional connectivity between these cortical areas, the defining characteristic of modules in a pain network.

Spatial neglect during electrocortical stimulation mapping in the right hemisphere.

Spatial processing was assessed following implantation of subdural electrodes in the nondominant hemisphere with electrocortical stimulation mapping (ESM) in two patients before epilepsy surgery. The first patient had mild hemispatial neglect/extinction during ESM of posterior temporal and inferior parietal areas. These areas were resected, and the patient had postoperative deficits that were similar to those occurring with ESM. The second patient was found to have marked hemispatial neglect during stimulation of parietal areas. These areas were not resected, and the patient had no neglect following surgery. These results suggest that ESM can help predict spatial processing deficits associated with cortical resection, and may help prevent postoperative impairments following resection in right parietal or temporal regions.